StemCell Therapy

Gene therapy is a rapidly growing field of medicine in which genes are introduced into the body to treat diseases. Genes control heredity and provide the basic biological code for determining a cell's specific functions. Gene therapy seeks to provide genes that correct or supplant the disease-controlling functions of cells that are not, in essence, doing their job. Somatic gene therapy introduces therapeutic genes at the tissue or cellular level to treat a specific individual. Germ-line gene therapy inserts genes into reproductive cells or possibly into embryos to correct genetic defects that could be passed on to future generations. Initially conceived as an approach for treating inherited diseases, like cystic fibrosis and Huntington's disease, the scope of potential gene therapies has grown to include treatments for cancers, arthritis, and infectious diseases. Although gene therapy testing in humans has advanced rapidly, many questions surround its use. For example, some scientists are concerned that the therapeutic genes themselves may cause disease. Others fear that germ-line gene therapy may be used to control human development in ways not connected with disease, like intelligence or appearance.

Gene therapy has grown out of the science of genetics or how heredity works. Scientists know that life begins in a cell, the basic building block of all multicellular organisms. Humans, for instance, are made up of trillions of cells, each performing a specific function. Within the cell's nucleus (the center part of a cell that regulates its chemical functions) are pairs of chromosomes. These threadlike structures are made up of a single molecule of DNA (deoxyribonucleic acid), which carries the blueprint of life in the form of codes, or genes, that determine inherited characteristics.

A DNA molecule looks like two ladders with one of the sides taken off both and then twisted around each other. The rungs of these ladders meet (resulting in a spiral staircase-like structure) and are called base pairs. Base pairs are made up of nitrogen molecules and arranged in specific sequences. Millions of these base pairs, or sequences, can make up a single gene, specifically defined as a segment of the chromosome and DNA that contains certain hereditary information. The gene, or combination of genes formed by these base pairs ultimately direct an organism's growth and characteristics through the production of certain chemicals, primarily proteins, which carry out most of the body's chemical functions and biological reactions.

Scientists have long known that alterations in genes present within cells can cause inherited diseases like cystic fibrosis, sickle-cell anemia, and hemophilia. Similarly, errors in the total number of chromosomes can cause conditions such as Down syndrome or Turner's syndrome. As the study of genetics advanced, however, scientists learned that an altered genetic sequence also can make people more susceptible to diseases, like atherosclerosis, cancer, and even schizophrenia. These diseases have a genetic component, but also are influenced by environmental factors (like diet and lifestyle). The objective of gene therapy is to treat diseases by introducing functional genes into the body to alter the cells involved in the disease process by either replacing missing genes or providing copies of functioning genes to replace nonfunctioning ones. The inserted genes can be naturally-occurring genes that produce the desired effect or may be genetically engineered (or altered) genes.

Scientists have known how to manipulate a gene's structure in the laboratory since the early 1970s through a process called gene splicing. The process involves removing a fragment of DNA containing the specific genetic sequence desired, then inserting it into the DNA of another gene. The resultant product is called recombinant DNA and the process is genetic engineering.

There are basically two types of gene therapy. Germ-line gene therapy introduces genes into reproductive cells (sperm and eggs) or someday possibly into embryos in hopes of correcting genetic abnormalities that could be passed on to future generations. Most of the current work in applying gene therapy, however, has been in the realm of somatic gene therapy. In this type of gene therapy, therapeutic genes are inserted into tissue or cells to produce a naturally occurring protein or substance that is lacking or not functioning correctly in an individual patient.

In both types of therapy, scientists need something to transport either the entire gene or a recombinant DNA to the cell's nucleus, where the chromosomes and DNA reside. In essence, vectors are molecular delivery trucks. One of the first and most popular vectors developed were viruses because they invade cells as part of the natural infection process. Viruses have the potential to be excellent vectors because they have a specific relationship with the host in that they colonize certain cell types and tissues in specific organs. As a result, vectors are chosen according to their attraction to certain cells and areas of the body.

One of the first vectors used was retroviruses. Because these viruses are easily cloned (artificially reproduced) in the laboratory, scientists have studied them extensively and learned a great deal about their biological action. They also have learned how to remove the genetic information that governs viral replication, thus reducing the chances of infection.

Retroviruses work best in actively dividing cells, but cells in the body are relatively stable and do not divide often. As a result, these cells are used primarily for ex vivo (outside the body) manipulation. First, the cells are removed from the patient's body, and the virus, or vector, carrying the gene is inserted into them. Next, the cells are placed into a nutrient culture where they grow and replicate. Once enough cells are gathered, they are returned to the body, usually by injection into the blood stream. Theoretically, as long as these cells survive, they will provide the desired therapy.

Another class of viruses, called the adenoviruses, also may prove to be good gene vectors. These viruses can effectively infect nondividing cells in the body, where the desired gene product then is expressed naturally. In addition to being a more efficient approach to gene transportation, these viruses, which cause respiratory infections, are more easily purified and made stable than retroviruses, resulting in less chance of an unwanted viral infection. However, these viruses live for several days in the body, and some concern surrounds the possibility of infecting others with the viruses through sneezing or coughing. Other viral vectors include influenza viruses, Sindbis virus, and a herpes virus that infects nerve cells.

Scientists also have delved into nonviral vectors. These vectors rely on the natural biological process in which cells uptake (or gather) macromolecules. One approach is to use liposomes, globules of fat produced by the body and taken up by cells. Scientists also are investigating the introduction of raw recombinant DNA by injecting it into the bloodstream or placing it on microscopic beads of gold shot into the skin with a "gene-gun." Another possible vector under development is based on dendrimer molecules. A class of polymers (naturally occurring or artificial substances that have a high molecular weight and formed by smaller molecules of the same or similar substances), is "constructed" in the laboratory by combining these smaller molecules. They have been used in manufacturing Styrofoam, polyethylene cartons, and Plexiglass. In the laboratory, dendrimers have shown the ability to transport genetic material into human cells. They also can be designed to form an affinity for particular cell membranes by attaching to certain sugars and protein groups.

In the early 1970s, scientists proposed "gene surgery" for treating inherited diseases caused by faulty genes. The idea was to take out the disease-causing gene and surgically implant a gene that functioned properly. Although sound in theory, scientists, then and now, lack the biological knowledge or technical expertise needed to perform such a precise surgery in the human body.

However, in 1983, a group of scientists from Baylor College of Medicine in Houston, Texas, proposed that gene therapy could one day be a viable approach for treating Lesch-Nyhan disease, a rare neurological disorder. The scientists conducted experiments in which an enzyme-producing gene (a specific type of protein) for correcting the disease was injected into a group of cells for replication. The scientists theorized the cells could then be injected into people with Lesch-Nyhan disease, thus correcting the genetic defect that caused the disease.

As the science of genetics advanced throughout the 1980s, gene therapy gained an established foothold in the minds of medical scientists as a promising approach to treatments for specific diseases. One of the major reasons for the growth of gene therapy was scientists' increasing ability to identify the specific genetic malfunctions that caused inherited diseases. Interest grew as further studies of DNA and chromosomes (where genes reside) showed that specific genetic abnormalities in one or more genes occurred in successive generations of certain family members who suffered from diseases like intestinal cancer, bipolar disorder, Alzheimer's disease, heart disease, diabetes, and many more. Although the genes may not be the only cause of the disease in all cases, they may make certain individuals more susceptible to developing the disease because of environmental influences, like smoking, pollution, and stress. In fact, some scientists theorize that all diseases may have a genetic component.

On September 14, 1990, a four-year old girl suffering from a genetic disorder that prevented her body from producing a crucial enzyme became the first person to undergo gene therapy in the United States. Because her body could not produce adenosine deaminase (ADA), she had a weakened immune system, making her extremely susceptible to severe, life-threatening infections. W. French Anderson and colleagues at the National Institutes of Health's Clinical Center in Bethesda, Maryland, took white blood cells (which are crucial to proper immune system functioning) from the girl, inserted ADA producing genes into them, and then transfused the cells back into the patient. Although the young girl continued to show an increased ability to produce ADA, debate arose as to whether the improvement resulted from the gene therapy or from an additional drug treatment she received.

Nevertheless, a new era of gene therapy began as more and more scientists sought to conduct clinical trial (testing in humans) research in this area. In that same year, gene therapy was tested on patients suffering from melanoma (skin cancer). The goal was to help them produce antibodies (disease fighting substances in the immune system) to battle the cancer.

These experiments have spawned an ever growing number of attempts at gene therapies designed to perform a variety of functions in the body. For example, a gene therapy for cystic fibrosis aims to supply a gene that alters cells, enabling them to produce a specific protein to battle the disease. Another approach was used for brain cancer patients, in which the inserted gene was designed to make the cancer cells more likely to respond to drug treatment. Another gene therapy approach for patients suffering from artery blockage, which can lead to strokes, induces the growth of new blood vessels near clogged arteries, thus ensuring normal blood circulation.

Currently, there are a host of new gene therapy agents in clinical trials. In the United States, both nucleic acid based (in vivo ) treatments and cell-based (ex vivo ) treatments are being investigated. Nucleic acid based gene therapy uses vectors (like viruses) to deliver modified genes to target cells. Cell-based gene therapy techniques remove cells from the patient in order to genetically alter them then reintroduce them to the patient's body. Presently, gene therapies for the following diseases are being developed: cystic fibrosis (using adenoviral vector), HIV infection (cell-based), malignant melanoma (cell-based), Duchenne muscular dystrophy (cell-based), hemophilia B (cell-based), kidney cancer (cell-based), Gaucher's Disease (retroviral vector), breast cancer (retroviral vector), and lung cancer (retroviral vector). When a cell or individual is treated using gene therapy and successful incorporation of engineered genes has occurred, the cell or individual is said to be transgenic.

The medical establishment's contribution to transgenic research has been supported by increased government funding. In 1991, the U.S. government provided $58 million for gene therapy research, with increases in funding of $15-40 million dollars a year over the following four years. With fierce competition over the promise of societal benefit in addition to huge profits, large pharmaceutical corporations have moved to the forefront of transgenic research. In an effort to be first in developing new therapies, and armed with billions of dollars of research funds, such corporations are making impressive strides toward making gene therapy a viable reality in the treatment of once elusive diseases.

The potential scope of gene therapy is enormous. More than 4,200 diseases have been identified as resulting directly from abnormal genes, and countless others that may be partially influenced by a person's genetic makeup. Initial research has concentrated on developing gene therapies for diseases whose genetic origins have been established and for other diseases that can be cured or improved by substances genes produce.

The following are examples of potential gene therapies. People suffering from cystic fibrosis lack a gene needed to produce a salt-regulating protein. This protein regulates the flow of chloride into epithelial cells, (the cells that line the inner and outer skin layers) that cover the air passages of the nose and lungs. Without this regulation, patients with cystic fibrosis build up a thick mucus that makes them prone to lung infections. A gene therapy technique to correct this abnormality might employ an adenovirus to transfer a normal copy of what scientists call the cystic fibrosis transmembrane conductance regulator, or CTRF, gene. The gene is introduced into the patient by spraying it into the nose or lungs. Researchers announced in 2004 that they had, for the first time, treated a dominant neurogenerative disease called Spinocerebella ataxia type 1, with gene therapy. This could lead to treating similar diseases such as Huntingtons disease. They also announced a single intravenous injection could deliver therapy to all muscles, perhaps providing hope to people with muscular dystrophy.

Familial hypercholesterolemia (FH) also is an inherited disease, resulting in the inability to process cholesterol properly, which leads to high levels of artery-clogging fat in the blood stream. Patients with FH often suffer heart attacks and strokes because of blocked arteries. A gene therapy approach used to battle FH is much more intricate than most gene therapies because it involves partial surgical removal of patients' livers (ex vivo transgene therapy). Corrected copies of a gene that serve to reduce cholesterol build-up are inserted into the liver sections, which then are transplanted back into the patients.

Gene therapy also has been tested on patients with AIDS. AIDS is caused by the human immunodeficiency virus (HIV), which weakens the body's immune system to the point that sufferers are unable to fight off diseases like pneumonias and cancer. In one approach, genes that produce specific HIV proteins have been altered to stimulate immune system functioning without causing the negative effects that a complete HIV molecule has on the immune system. These genes are then injected in the patient's blood stream. Another approach to treating AIDS is to insert, via white blood cells, genes that have been genetically engineered to produce a receptor that would attract HIV and reduce its chances of replicating. In 2004, researchers reported that had developed a new vaccine concept for HIV, but the details were still in development.

Several cancers also have the potential to be treated with gene therapy. A therapy tested for melanoma, or skin cancer, involves introducing a gene with an anticancer protein called tumor necrosis factor (TNF) into test tube samples of the patient's own cancer cells, which are then reintroduced into the patient. In brain cancer, the approach is to insert a specific gene that increases the cancer cells' susceptibility to a common drug used in fighting the disease. In 2003, researchers reported that they had harnessed the cell killing properties of adenoviruses to treat prostate cancer. A 2004 report said that researchers had developed a new DNA vaccine that targeted the proteins expressed in cervical cancer cells.

Gaucher disease is an inherited disease caused by a mutant gene that inhibits the production of an enzyme called glucocerebrosidase. Patients with Gaucher disease have enlarged livers and spleens and eventually their bones deteriorate. Clinical gene therapy trials focus on inserting the gene for producing this enzyme.

Gene therapy also is being considered as an approach to solving a problem associated with a surgical procedure known as balloon angioplasty. In this procedure, a stent (in this case, a type of tubular scaffolding) is used to open the clogged artery. However, in response to the trauma of the stent insertion, the body initiates a natural healing process that produces too many cells in the artery and results in restenosis, or reclosing of the artery. The gene therapy approach to preventing this unwanted side effect is to cover the outside of the stents with a soluble gel. This gel contains vectors for genes that reduce this overactive healing response.

Regularly throughout the past decade, and no doubt over future years, scientists have and will come up with new possible ways for gene therapy to help treat human disease. Recent advancements include the possibility of reversing hearing loss in humans with experimental growing of new sensory cells in adult guinea pigs, and avoiding amputation in patients with severe circulatory problems in their legs with angiogenic growth factors.

Although great strides have been made in gene therapy in a relatively short time, its potential usefulness has been limited by lack of scientific data concerning the multitude of functions that genes control in the human body. For instance, it is now known that the vast majority of genetic material does not store information for the creation of proteins, but rather is involved in the control and regulation of gene expression, and is, thus, much more difficult to interpret. Even so, each individual cell in the body carries thousands of genes coding for proteins, with some estimates as high as 150,000 genes. For gene therapy to advance to its full potential, scientists must discover the biological role of each of these individual genes and where the base pairs that make them up are located on DNA.

To address this issue, the National Institutes of Health initiated the Human Genome Project in 1990. Led by James D. Watson (one of the co-discoverers of the chemical makeup of DNA) the project's 15-year goal is to map the entire human genome (a combination of the words gene and chromosomes). A genome map would clearly identify the location of all genes as well as the more than three billion base pairs that make them up. With a precise knowledge of gene locations and functions, scientists may one day be able to conquer or control diseases that have plagued humanity for centuries.

Scientists participating in the Human Genome Project identified an average of one new gene a day, but many expected this rate of discovery to increase. By the year 2005, their goal was to determine the exact location of all the genes on human DNA and the exact sequence of the base pairs that make them up. Some of the genes identified through this project include a gene that predisposes people to obesity, one associated with programmed cell death (apoptosis), a gene that guides HIV viral reproduction, and the genes of inherited disorders like Huntington's disease, Lou Gehrig's disease, and some colon and breast cancers. In April 2003, the finished sequence was announced, with 99% of the human genome's gene-containing regions mapped to an accuracy of 99.9%.

Gene therapy seems elegantly simple in its concept: supply the human body with a gene that can correct a biological malfunction that causes a disease. However, there are many obstacles and some distinct questions concerning the viability of gene therapy. For example, viral vectors must be carefully controlled lest they infect the patient with a viral disease. Some vectors, like retroviruses, also can enter cells functioning properly and interfere with the natural biological processes, possibly leading to other diseases. Other viral vectors, like the adenoviruses, often are recognized and destroyed by the immune system so their therapeutic effects are short-lived. Maintaining gene expression so it performs its role properly after vector delivery is difficult. As a result, some therapies need to be repeated often to provide long-lasting benefits.

One of the most pressing issues, however, is gene regulation. Genes work in concert to regulate their functioning. In other words, several genes may play a part in turning other genes on and off. For example, certain genes work together to stimulate cell division and growth, but if these are not regulated, the inserted genes could cause tumor formation and cancer. Another difficulty is learning how to make the gene go into action only when needed. For the best and safest therapeutic effort, a specific gene should turn on, for example, when certain levels of a protein or enzyme are low and must be replaced. But the gene also should remain dormant when not needed to ensure it doesn't oversupply a substance and disturb the body's delicate chemical makeup.

One approach to gene regulation is to attach other genes that detect certain biological activities and then react as a type of automatic off-and-on switch that regulates the activity of the other genes according to biological cues. Although still in the rudimentary stages, researchers are making headway in inhibiting some gene functioning by using a synthetic DNA to block gene transcriptions (the copying of genetic information). This approach may have implications for gene therapy.

While gene therapy holds promise as a revolutionary approach to treating disease, ethical concerns over its use and ramifications have been expressed by scientists and lay people alike. For example, since much needs to be learned about how these genes actually work and their long-term effect, is it ethical to test these therapies on humans, where they could have a disastrous result? As with most clinical trials concerning new therapies, including many drugs, the patients participating in these studies usually have not responded to more established therapies and often are so ill the novel therapy is their only hope for long-term survival.

Another questionable outgrowth of gene therapy is that scientists could possibly manipulate genes to genetically control traits in human offspring that are not health related. For example, perhaps a gene could be inserted to ensure that a child would not be bald, a seemingly harmless goal. However, what if genetic manipulation was used to alter skin color, prevent homosexuality, or ensure good looks? If a gene is found that can enhance intelligence of children who are not yet born, will everyone in society, the rich and the poor, have access to the technology or will it be so expensive only the elite can afford it?

The Human Genome Project, which plays such an integral role for the future of gene therapy, also has social repercussions. If individual genetic codes can be determined, will such information be used against people? For example, will someone more susceptible to a disease have to pay higher insurance premiums or be denied health insurance altogether? Will employers discriminate between two potential employees, one with a "healthy" genome and the other with genetic abnormalities?

Some of these concerns can be traced back to the eugenics movement popular in the first half of the twentieth century. This genetic "philosophy" was a societal movement that encouraged people with "positive" traits to reproduce while those with less desirable traits were sanctioned from having children. Eugenics was used to pass strict immigration laws in the United States, barring less suitable people from entering the country lest they reduce the quality of the country's collective gene pool. Probably the most notorious example of eugenics in action was the rise of Nazism in Germany, which resulted in the Eugenic Sterilization Law of 1933. The law required sterilization for those suffering from certain disabilities and even for some who were simply deemed "ugly." To ensure that this novel science is not abused, many governments have established organizations specifically for overseeing the development of gene therapy. In the United States, the Food and Drug Administration (FDA) and the National Institutes of Health require scientists to take a precise series of steps and meet stringent requirements before proceeding with clinical trials. As of mid-2004, more than 300 companies were carrying out gene medicine developments and 500 clinical trials were underway. How to deliver the therapy is the key to unlocking many of the researchers discoveries.

In fact, gene therapy has been immersed in more controversy and surrounded by more scrutiny in both the health and ethical arena than most other technologies (except, perhaps, for cloning) that promise to substantially change society. Despite the health and ethical questions surrounding gene therapy, the field will continue to grow and is likely to change medicine faster than any previous medical advancement.

Cell The smallest living unit of the body that groups together to form tissues and help the body perform specific functions.

Chromosome A microscopic thread-like structure found within each cell of the body, consisting of a complex of proteins and DNA. Humans have 46 chromosomes arranged into 23 pairs. Changes in either the total number of chromosomes or their shape and size (structure) may lead to physical or mental abnormalities.

Clinical trial The testing of a drug or some other type of therapy in a specific population of patients.

Clone A cell or organism derived through asexual (without sex) reproduction containing the identical genetic information of the parent cell or organism.

Deoxyribonucleic acid (DNA) The genetic material in cells that holds the inherited instructions for growth, development, and cellular functioning.

Embryo The earliest stage of development of a human infant, usually used to refer to the first eight weeks of pregnancy. The term fetus is used from roughly the third month of pregnancy until delivery.

Enzyme A protein that causes a biochemical reaction or change without changing its own structure or function.

Eugenics A social movement in which the population of a society, country, or the world is to be improved by controlling the passing on of hereditary information through mating.

Gene A building block of inheritance, which contains the instructions for the production of a particular protein, and is made up of a molecular sequence found on a section of DNA. Each gene is found on a precise location on a chromosome.

Gene transcription The process by which genetic information is copied from DNA to RNA, resulting in a specific protein formation.

Genetic engineering The manipulation of genetic material to produce specific results in an organism.

Genetics The study of hereditary traits passed on through the genes.

Germ-line gene therapy The introduction of genes into reproductive cells or embryos to correct inherited genetic defects that can cause disease.

Liposome Fat molecule made up of layers of lipids.

Macromolecules A large molecule composed of thousands of atoms.

Nitrogen A gaseous element that makes up the base pairs in DNA.

Nucleus The central part of a cell that contains most of its genetic material, including chromosomes and DNA.

Protein Important building blocks of the body, composed of amino acids, involved in the formation of body structures and controlling the basic functions of the human body.

Somatic gene therapy The introduction of genes into tissue or cells to treat a genetic related disease in an individual.

Vectors Something used to transport genetic information to a cell.

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National Human Genome Research Institute. The National Institutes of Health. 9000 Rockville Pike, Bethesda, MD 20892. (301) 496-2433. http://www.nhgri.nih.gov.

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gene therapy facts, information, pictures | Encyclopedia.com ...

Gene therapy delivers DNA into a patients cells to replace faulty or missing genes or adds new genes in an attempt to cure diseases or to make changes so the body is better able to fight off disease. The DNA for a gene or genes is carried into a patients cells by a delivery vehicle called a vector, typically a specially engineered virus. The vector then inserts the gene(s) into the cells' DNA.

Although gene therapy is relatively new and often still considered experimental, it can provide a cure for life-threatening diseases that dont respond well to other therapies (including immunodeficiencies, metabolic disorders, and relapsed cancers) and for acute conditions that currently rely on complex and expensive life-long medication and management (such as sickle cell disease and hemophilia).

Our Gene Therapy Clinical Trials

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Dana-Farber/Boston Childrens has one the most extensive and long-running pediatric gene therapy programs in the world. Since 2010, we have treated 25 patients from 11 countries through eight gene therapy clinical trials.

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Gene Therapy for Pediatric Diseases | DNA Therapy - Dana ...

Despite bouncing off a 2-year low, biotech is still an unpopular sector and investors are rightfully concerned about its near-term prospects. Recent drug failures, growing pricing pressure and the potential impact of biosimilars all contribute to the negative sentiment, but the main problem is the lack of growth drivers for the remainder of 2016 (and potentially 2017).

The biotech industry relies on innovation cycles to create new revenue sources. This was the case in the 2013-2014 biotech bull market, which was driven by a wave of medical breakthroughs (PD-1, HCV, CAR/TCR, oral MS drugs, CF etc.). These waves typically involve new therapeutic approaches coupled with disruptive technologies as their enablers.

In oncology, for example, the understanding that cancer is driven by aberrant signaling coupled with advances in medicinal chemistry and antibody engineering led to the development of kinase inhibitors and monoclonal antibodies as blockers of signaling. A decade later, insights around cancer immunology gave rise to the immuno-oncology field and PD-1 inhibitors in particular, which are expected to become the biggest oncology franchise ever.

Gene therapy ticks all the boxes

While there are several hot areas in biotech such as gene editing and microbiome, most are still early and their applicability is unclear. Gene therapy, on the other hand, is more mature and de-risked with tens of clinical studies and the potential to treat (and perhaps cure) a wide range of diseases where treatment is inadequate or non-existent. The commercial upside from these programs is huge and should expand as additional indications are pursued.

As I previously discussed, the past two years saw a surge in the number of clinical-stage gene therapies, some of which already generated impressive efficacy across multiple indications. This makes gene therapy the only truly disruptive field which is mature enough not only from a technology but also from a clinical standpoint. Importantly, most studies are conducted by companies according to industry and regulatory standards, in contrast to historical gene therapy studies that were run by academic groups.

To me, the striking thing about the results is the breadth of technologies, indications and modes of administrations evaluated to date. This versatility is very important for the future of gene therapy as it reduces overall development risk and increases likelihood of success by allowing companies to tailor the right product for each indication. Parameters include mode of administration (local vs. systemic vs. ex vivo), tropism for the target tissue (eye, bone marrow, liver etc.), immunogenicity and onset of activity.

Building a diversified gene therapy basket

Given the early development stage and large number of technologies, I prefer to own a basket of gene therapy stocks with a focus on the more clinically validated ones: Spark (ONCE), Bluebird (BLUE) and Avexis (AVXS).

Bluebird and Spark are the most further along (and also the largest based on market cap) gene therapy companies and should be the basis for any gene therapy portfolio. With two completely different technologies, the two companies have strong clinical proof-of-concept for their respective lead programs.

Avexis is less advanced without a clinically validated product, but recent data for its lead program are too promising to ignore.

Spark Clinical validation for retinal and liver indications

Sparks lead programs (SPK-RPE65) will probably become the first gene therapy to get FDA approval. In October, the company reported strong P3 data in rare genetic retinal conditions caused by RPE65 mutations, the first randomized and statistically significant data for a gene therapy. The company is expected to complete its BLA submission later in 2016 which should lead to FDA approval in 2017. Sparks second ophthalmology program for choroideremia is in P1 with efficacy data expected later in 2016.

Earlier this month, Spark released an encouraging update for its Hemophilia B program, SPK-9001 (partnered with Pfizer [PFE]). A single administration of SPK-9001 led to a sustained and clinically meaningful production of Factor IX, a clotting factor which is dysfunctional in Hemophilia B patients. All four treated patients experienced a clinically significant increase in Factor IX activity from <2% to 26%-41% (12% is predicted to be sufficient for minimizing incidence bleeding events). Due to the limited follow up (under 6 months), durability is still an open question.

Spark intends to advance its wholly-owned Hemophilia A program (SPK-8011) to the clinic later in 2016 with initial data expected in H1:2017. Results in the Hemophilia B should be viewed as a positive read-through but Hemophilia A still presents certain technical challenges (e.g. missing protein is several fold larger) which required Spark to use a different vector. Hemophilia A represents a $5B opportunity compared to $1B for Hemophilia B.

Bluebird

Despite being one of the worst biotech performers, Bluebird remains the largest and most visible gene therapy company. In contrast to most gene therapy companies, Bluebird treats patients cells ex-vivo (outside of the body) in a process that resembles stem cell transplant or adoptive cell transfer (CAR, TCR). Progenitor cells are collected from the patient, a genetic modification is integrated into the genome followed by infusion of the cells that repopulate the bone marrow. This enables Bluebird to go after hematologic diseases like beta thalassemia and Sickle-cell disease (SCD) where target cells are constantly dividing.

Sentiment around Bluebirds lead program, Lenti-globin , plummeted last year after a series of disappointing results in a subset of beta-thal patients and preliminary data in SCD, which represents the more important commercial opportunity. Particularly in SCD patients, post-treatment hemoglobin levels were relatively low and although some increase has been noted with time, it is still unclear what the maximal effect would be. Market reaction was brutal, sending shares down 75% in just over a year.

Next update for Lenti-globin is expected at ASH in December. Despite the disappointing efficacy observed in SCD and beta-thal, I am cautiously optimistic about Bluebirds efforts to optimize treatment protocols and regimens. These include specific conditioning regimens and ex-vivo treatment of cells that may improve transduction rate and hemoglobin production in patients. Some of these modifications are already being implemented in newly recruited patients and hopefully longer follow up will lead to higher hemoglobin levels in already-reported patients.

The only clinical update so far in 2016 was for Lenti-D in C-ALD, a rare neurological disease that affects infants in their first years. Results demonstrated that of 17 patients treated to date (median follow-up of 16 months), all remain alive and free of major functional deterioration (defined as major functional disabilities, MFD). The primary endpoint, defined as no MFD at 2 years, was reached for 3/3 patients with sufficient follow-up and assuming the trend continues Bluebird may be in a position to file for approval in H2:2017.

Lenti-Ds commercial opportunity is limited (200 patients diagnosed each year in developed countries) so investors understandably focus on Lenti-globin, which is being developed for beta thal (~20k patients in developed countries) and SCD (~160k patients).

Bluebird is expected to end 2016 with ~$650M in cash. Current market cap is $1.7B.

Avexis

Avexis is developing AVXS-101 for Spinal muscular atrophy Type 1 (SMA1), a rapidly deteriorating and fatal neuro-muscular disease. SMA1 is characterized by rapid deterioration in motor and neuronal functions with 50% of patients experiencing death or permanent ventilation by their first anniversary. Most patients die from respiratory failure by the age of two. SMA Type 2 and Type 3 are also caused by SMN1 mutations and are characterized by a later onset and milder disease burden (but unmet need is still significant in these indications). The US prevalence of SMA is 10,000, 600 of which are SMA1.

In contrast to Bluebird and Spark, Avexis does not have conclusive proof it can lead to expression of the missing protein (SMN1) in the target tissue nor does it have randomized clinical data but the results generated to date are simply too provocative to ignore.

At the most recent update, Avexis presented data for 15 patients who received AVXS-101 in their first months of life. 3 patients were treated with a low dose and 12 were treated with a high dose. Strikingly, none of the children experienced an event (defined as ventilation or death), including patients who reached 2 years of age. All 9 patients with sufficient follow up, reached the age of 13.6 months without an event in contrast to historical data that show an event-free survival of 25%. AVXS-101 also led to a dose dependent increase in motor function which had a quick onset especially at the higher dose.

As with any results from an open label study without a control arm, these data should be analyzed with caution, as they need to be corroborated by large controlled studies (expected to start next year). Still, the data point to an overwhelming benefit in a very aggressive disease. One of the most exciting aspects of this program is the fact that it is given systemically via IV administration, which implies the treatment reaches the neurons in the CNS. Avexis plans to start a trial in SMA2 in H2:16 using intrathecal delivery (directly to the spinal canal). This decision is surprising given the results with IV administration in SMA1 and the fact that the BBB immaturity hypothesis in babies is not considered relevant anymore. (See this review)

AVXS-101s main competitor is Biogens (BIIB) and Ionis (IONS) nusinersen, an antisense molecule that needs to be intrathecally injected 3-4 times a year. As both drugs generated encouraging clinical data in small non-randomized studies, it is hard to compare them, however, AVXS-101 has an obvious advantage of being a potentially one time IV injection. Nusinersen is in P3 with topline data expected in mid-2017.

AVXS-101 is based on an AAV9 vector developed by REGENXBIO (RGNX), which licensed the technology to Avexis. Beyond the 5%-10% in royalties REGENXBIO is eligible to receive, data for AVXS-101 bode well for the companys proprietary programs in MPS-I and MPS-II, two other rare diseases with neurological involvement where BBB penetration is crucial. These programs are also based on REGENXBIOs AAV9.

Beyond AVXS-101, REGENXBIO has an impressive partnered pipeline which includes collaborations with Voyager (VYGR), Dimension (DMTX) , Baxalta and Lysogene.

Portfolio updates Immunogen, Marinus, Esperion

June was a rough month for three of my holdings. Immunogen (IMGN) had a disappointing data set at ASCO, Marinus (MRNS) reported a P3 failure in epilepsy and most recently, Esperion was dealt a regulatory blow from the FDA that may push development timelines by several years. I am selling Immunogen and Marinus due to the lack of near-term catalysts although long-term their respective drugs could still be valuable. I decided to keep Esperion as I still find ETC-1002 very attractive and hope that PCSK9s CVOT data will soften FDAs concerns about LDL-C reduction as an approvable endpoint.

Three additional companies with important binary readouts in the coming months are Array Biopharma (ARRY), SAGE (SAGE) and Aurinia (AUPH). Array will have P3 data for selumetinib (partnered with AstraZeneca) in KRAS+ NSCLC. SAGE will report data from a randomized P2 in PPD following a promising single-arm data set. Aurinia will report results from the AURA study in lupus nephritis patients, where there is a strong rationale for using the companys drug (voclosporin) but limited direct clinical validation.

Portfolio holdings July 4, 2016

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Could gene therapy become biotechs growth driver in 2017 ...

Virtually all cells in the human body contain genes, making them potential targets for gene therapy. However, these cells can be divided into two major categories: somatic cells (most cells of the body) or cells of the germline (eggs or sperm). In theory it is possible to transform either somatic cells or germ cells.

Gene therapy using germ line cells results in permanent changes that are passed down to subsequent generations. If done early in embryologic development, such as during preimplantation diagnosis and in vitro fertilization, the gene transfer could also occur in all cells of the developing embryo. The appeal of germ line gene therapy is its potential for offering a permanent therapeutic effect for all who inherit the target gene. Successful germ line therapies introduce the possibility of eliminating some diseases from a particular family, and ultimately from the population, forever. However, this also raises controversy. Some people view this type of therapy as unnatural, and liken it to "playing God." Others have concerns about the technical aspects. They worry that the genetic change propagated by germ line gene therapy may actually be deleterious and harmful, with the potential for unforeseen negative effects on future generations.

Somatic cells are nonreproductive. Somatic cell therapy is viewed as a more conservative, safer approach because it affects only the targeted cells in the patient, and is not passed on to future generations. In other words, the therapeutic effect ends with the individual who receives the therapy. However, this type of therapy presents unique problems of its own. Often the effects of somatic cell therapy are short-lived. Because the cells of most tissues ultimately die and are replaced by new cells, repeated treatments over the course of the individual's life span are required to maintain the therapeutic effect. Transporting the gene to the target cells or tissue is also problematic. Regardless of these difficulties, however, somatic cell gene therapy is appropriate and acceptable for many disorders, including cystic fibrosis, muscular dystrophy, cancer, and certain infectious diseases. Clinicians can even perform this therapy in utero, potentially correcting or treating a life-threatening disorder that may significantly impair a baby's health or development if not treated before birth.

In summary, the distinction is that the results of any somatic gene therapy are restricted to the actual patient and are not passed on to his or her children. All gene therapy to date on humans has been directed at somatic cells, whereas germline engineering in humans remains controversial and prohibited in for instance the European Union.

Somatic gene therapy can be broadly split into two categories:

More here:
Gene Therapy Technology Explanied

Gene therapy is the therapeutic delivery of nucleic acid polymers into a patient's cells as a drug to treat disease.[1] The first attempt at modifying human DNA was performed in 1980 by Martin Cline, but the first successful and approved[by whom?] nuclear gene transfer in humans was performed in May 1989.[2] The first therapeutic use of gene transfer as well as the first direct insertion of human DNA into the nuclear genome was performed by French Anderson in a trial starting in September 1990.

Between 1989 and February 2016, over 2,300 clinical trials had been conducted, more than half of them in phase I.[3]

It should be noted that not all medical procedures that introduce alterations to a patient's genetic makeup can be considered gene therapy. Bone marrow transplantation and organ transplants in general have been found to introduce foreign DNA into patients.[4] Gene therapy is defined by the precision of the procedure and the intention of direct therapeutic effects.

Gene therapy was conceptualized in 1972, by authors who urged caution before commencing human gene therapy studies.

The first attempt, an unsuccessful one, at gene therapy (as well as the first case of medical transfer of foreign genes into humans not counting organ transplantation) was performed by Martin Cline on 10 July 1980.[5][6] Cline claimed that one of the genes in his patients was active six months later, though he never published this data or had it verified[7] and even if he is correct, it's unlikely it produced any significant beneficial effects treating beta-thalassemia.[8]

After extensive research on animals throughout the 1980s and a 1989 bacterial gene tagging trial on humans, the first gene therapy widely accepted as a success was demonstrated in a trial that started on September 14, 1990, when Ashi DeSilva was treated for ADA-SCID.[9]

The first somatic treatment that produced a permanent genetic change was performed in 1993.[10]

This procedure was referred to sensationally and somewhat inaccurately in the media as a "three parent baby", though mtDNA is not the primary human genome and has little effect on an organism's individual characteristics beyond powering their cells.

Gene therapy is a way to fix a genetic problem at its source. The polymers are either translated into proteins, interfere with target gene expression, or possibly correct genetic mutations.

The most common form uses DNA that encodes a functional, therapeutic gene to replace a mutated gene. The polymer molecule is packaged within a "vector", which carries the molecule inside cells.

Early clinical failures led to dismissals of gene therapy. Clinical successes since 2006 regained researchers' attention, although as of 2014, it was still largely an experimental technique.[11] These include treatment of retinal diseases Leber's congenital amaurosis[12][13][14][15] and choroideremia,[16]X-linked SCID,[17] ADA-SCID,[18][19]adrenoleukodystrophy,[20]chronic lymphocytic leukemia (CLL),[21]acute lymphocytic leukemia (ALL),[22]multiple myeloma,[23]haemophilia[19] and Parkinson's disease.[24] Between 2013 and April 2014, US companies invested over $600 million in the field.[25]

The first commercial gene therapy, Gendicine, was approved in China in 2003 for the treatment of certain cancers.[26] In 2011 Neovasculgen was registered in Russia as the first-in-class gene-therapy drug for treatment of peripheral artery disease, including critical limb ischemia.[27] In 2012 Glybera, a treatment for a rare inherited disorder, became the first treatment to be approved for clinical use in either Europe or the United States after its endorsement by the European Commission.[11][28]

Following early advances in genetic engineering of bacteria, cells, and small animals, scientists started considering how to apply it to medicine. Two main approaches were considered replacing or disrupting defective genes.[29] Scientists focused on diseases caused by single-gene defects, such as cystic fibrosis, haemophilia, muscular dystrophy, thalassemia and sickle cell anemia. Glybera treats one such disease, caused by a defect in lipoprotein lipase.[28]

DNA must be administered, reach the damaged cells, enter the cell and express/disrupt a protein.[30] Multiple delivery techniques have been explored. The initial approach incorporated DNA into an engineered virus to deliver the DNA into a chromosome.[31][32]Naked DNA approaches have also been explored, especially in the context of vaccine development.[33]

Generally, efforts focused on administering a gene that causes a needed protein to be expressed. More recently, increased understanding of nuclease function has led to more direct DNA editing, using techniques such as zinc finger nucleases and CRISPR. The vector incorporates genes into chromosomes. The expressed nucleases then knock out and replace genes in the chromosome. As of 2014 these approaches involve removing cells from patients, editing a chromosome and returning the transformed cells to patients.[34]

Gene editing is a potential approach to alter the human genome to treat genetic diseases,[35] viral diseases,[36] and cancer.[37] As of 2016 these approaches were still years from being medicine.[38][39]

Gene therapy may be classified into two types:

In somatic cell gene therapy (SCGT), the therapeutic genes are transferred into any cell other than a gamete, germ cell, gametocyte or undifferentiated stem cell. Any such modifications affect the individual patient only, and are not inherited by offspring. Somatic gene therapy represents mainstream basic and clinical research, in which therapeutic DNA (either integrated in the genome or as an external episome or plasmid) is used to treat disease.

Over 600 clinical trials utilizing SCGT are underway in the US. Most focus on severe genetic disorders, including immunodeficiencies, haemophilia, thalassaemia and cystic fibrosis. Such single gene disorders are good candidates for somatic cell therapy. The complete correction of a genetic disorder or the replacement of multiple genes is not yet possible. Only a few of the trials are in the advanced stages.[40]

In germline gene therapy (GGT), germ cells (sperm or eggs) are modified by the introduction of functional genes into their genomes. Modifying a germ cell causes all the organism's cells to contain the modified gene. The change is therefore heritable and passed on to later generations. Australia, Canada, Germany, Israel, Switzerland and the Netherlands[41] prohibit GGT for application in human beings, for technical and ethical reasons, including insufficient knowledge about possible risks to future generations[41] and higher risks versus SCGT.[42] The US has no federal controls specifically addressing human genetic modification (beyond FDA regulations for therapies in general).[41][43][44][45]

The delivery of DNA into cells can be accomplished by multiple methods. The two major classes are recombinant viruses (sometimes called biological nanoparticles or viral vectors) and naked DNA or DNA complexes (non-viral methods).

In order to replicate, viruses introduce their genetic material into the host cell, tricking the host's cellular machinery into using it as blueprints for viral proteins. Scientists exploit this by substituting a virus's genetic material with therapeutic DNA. (The term 'DNA' may be an oversimplification, as some viruses contain RNA, and gene therapy could take this form as well.) A number of viruses have been used for human gene therapy, including retrovirus, adenovirus, lentivirus, herpes simplex, vaccinia and adeno-associated virus.[3] Like the genetic material (DNA or RNA) in viruses, therapeutic DNA can be designed to simply serve as a temporary blueprint that is degraded naturally or (at least theoretically) to enter the host's genome, becoming a permanent part of the host's DNA in infected cells.

Non-viral methods present certain advantages over viral methods, such as large scale production and low host immunogenicity. However, non-viral methods initially produced lower levels of transfection and gene expression, and thus lower therapeutic efficacy. Later technology remedied this deficiency[citation needed].

Methods for non-viral gene therapy include the injection of naked DNA, electroporation, the gene gun, sonoporation, magnetofection, the use of oligonucleotides, lipoplexes, dendrimers, and inorganic nanoparticles.

Some of the unsolved problems include:

Three patients' deaths have been reported in gene therapy trials, putting the field under close scrutiny. The first was that of Jesse Gelsinger in 1999.[52] One X-SCID patient died of leukemia in 2003.[9] In 2007, a rheumatoid arthritis patient died from an infection; the subsequent investigation concluded that the death was not related to gene therapy.[53]

In 1972 Friedmann and Roblin authored a paper in Science titled "Gene therapy for human genetic disease?"[54] Rogers (1970) was cited for proposing that exogenous good DNA be used to replace the defective DNA in those who suffer from genetic defects.[55]

In 1984 a retrovirus vector system was designed that could efficiently insert foreign genes into mammalian chromosomes.[56]

The first approved gene therapy clinical research in the US took place on 14 September 1990, at the National Institutes of Health (NIH), under the direction of William French Anderson.[57] Four-year-old Ashanti DeSilva received treatment for a genetic defect that left her with ADA-SCID, a severe immune system deficiency. The effects were temporary, but successful.[58]

Cancer gene therapy was introduced in 1992/93 (Trojan et al. 1993).[59] The treatment of glioblastoma multiforme, the malignant brain tumor whose outcome is always fatal, was done using a vector expressing antisense IGF-I RNA (clinical trial approved by NIH n 1602, and FDA in 1994). This therapy also represents the beginning of cancer immunogene therapy, a treatment which proves to be effective due to the anti-tumor mechanism of IGF-I antisense, which is related to strong immune and apoptotic phenomena.

In 1992 Claudio Bordignon, working at the Vita-Salute San Raffaele University, performed the first gene therapy procedure using hematopoietic stem cells as vectors to deliver genes intended to correct hereditary diseases.[60] In 2002 this work led to the publication of the first successful gene therapy treatment for adenosine deaminase-deficiency (SCID). The success of a multi-center trial for treating children with SCID (severe combined immune deficiency or "bubble boy" disease) from 2000 and 2002, was questioned when two of the ten children treated at the trial's Paris center developed a leukemia-like condition. Clinical trials were halted temporarily in 2002, but resumed after regulatory review of the protocol in the US, the United Kingdom, France, Italy and Germany.[61]

In 1993 Andrew Gobea was born with SCID following prenatal genetic screening. Blood was removed from his mother's placenta and umbilical cord immediately after birth, to acquire stem cells. The allele that codes for adenosine deaminase (ADA) was obtained and inserted into a retrovirus. Retroviruses and stem cells were mixed, after which the viruses inserted the gene into the stem cell chromosomes. Stem cells containing the working ADA gene were injected into Andrew's blood. Injections of the ADA enzyme were also given weekly. For four years T cells (white blood cells), produced by stem cells, made ADA enzymes using the ADA gene. After four years more treatment was needed.[citation needed]

Jesse Gelsinger's death in 1999 impeded gene therapy research in the US.[62][63] As a result, the FDA suspended several clinical trials pending the reevaluation of ethical and procedural practices.[64]

The modified cancer gene therapy strategy of antisense IGF-I RNA (NIH n 1602)[65] using antisense / triple helix anti IGF-I approach was registered in 2002 by Wiley gene therapy clinical trial - n 635 and 636. The approach has shown promising results in the treatment of six different malignant tumors: glioblastoma, cancers of liver, colon, prostate, uterus and ovary (Collaborative NATO Science Programme on Gene Therapy USA, France, Poland n LST 980517 conducted by J. Trojan) (Trojan et al., 2012). This antigene antisense/triple helix therapy has proven to be efficient, due to the mechanism stopping simultaneously IGF-I expression on translation and transcription levels, strengthening anti-tumor immune and apoptotic phenomena.

Sickle-cell disease can be treated in mice.[66] The mice which have essentially the same defect that causes human cases used a viral vector to induce production of fetal hemoglobin (HbF), which normally ceases to be produced shortly after birth. In humans, the use of hydroxyurea to stimulate the production of HbF temporarily alleviates sickle cell symptoms. The researchers demonstrated this treatment to be a more permanent means to increase therapeutic HbF production.[67]

A new gene therapy approach repaired errors in messenger RNA derived from defective genes. This technique has the potential to treat thalassaemia, cystic fibrosis and some cancers.[68]

Researchers created liposomes 25 nanometers across that can carry therapeutic DNA through pores in the nuclear membrane.[69]

In 2003 a research team inserted genes into the brain for the first time. They used liposomes coated in a polymer called polyethylene glycol, which, unlike viral vectors, are small enough to cross the bloodbrain barrier.[70]

Short pieces of double-stranded RNA (short, interfering RNAs or siRNAs) are used by cells to degrade RNA of a particular sequence. If a siRNA is designed to match the RNA copied from a faulty gene, then the abnormal protein product of that gene will not be produced.[71]

Gendicine is a cancer gene therapy that delivers the tumor suppressor gene p53 using an engineered adenovirus. In 2003, it was approved in China for the treatment of head and neck squamous cell carcinoma.[26]

In March researchers announced the successful use of gene therapy to treat two adult patients for X-linked chronic granulomatous disease, a disease which affects myeloid cells and damages the immune system. The study is the first to show that gene therapy can treat the myeloid system.[72]

In May a team reported a way to prevent the immune system from rejecting a newly delivered gene.[73] Similar to organ transplantation, gene therapy has been plagued by this problem. The immune system normally recognizes the new gene as foreign and rejects the cells carrying it. The research utilized a newly uncovered network of genes regulated by molecules known as microRNAs. This natural function selectively obscured their therapeutic gene in immune system cells and protected it from discovery. Mice infected with the gene containing an immune-cell microRNA target sequence did not reject the gene.

In August scientists successfully treated metastatic melanoma in two patients using killer T cells genetically retargeted to attack the cancer cells.[74]

In November researchers reported on the use of VRX496, a gene-based immunotherapy for the treatment of HIV that uses a lentiviral vector to deliver an antisense gene against the HIV envelope. In a phase I clinical trial, five subjects with chronic HIV infection who had failed to respond to at least two antiretroviral regimens were treated. A single intravenous infusion of autologous CD4 T cells genetically modified with VRX496 was well tolerated. All patients had stable or decreased viral load; four of the five patients had stable or increased CD4 T cell counts. All five patients had stable or increased immune response to HIV antigens and other pathogens. This was the first evaluation of a lentiviral vector administered in a US human clinical trial.[75][76]

In May researchers announced the first gene therapy trial for inherited retinal disease. The first operation was carried out on a 23-year-old British male, Robert Johnson, in early 2007.[77]

Leber's congenital amaurosis is an inherited blinding disease caused by mutations in the RPE65 gene. The results of a small clinical trial in children were published in April.[12] Delivery of recombinant adeno-associated virus (AAV) carrying RPE65 yielded positive results. In May two more groups reported positive results in independent clinical trials using gene therapy to treat the condition. In all three clinical trials, patients recovered functional vision without apparent side-effects.[12][13][14][15]

In September researchers were able to give trichromatic vision to squirrel monkeys.[78] In November 2009, researchers halted a fatal genetic disorder called adrenoleukodystrophy in two children using a lentivirus vector to deliver a functioning version of ABCD1, the gene that is mutated in the disorder.[79]

An April paper reported that gene therapy addressed achromatopsia (color blindness) in dogs by targeting cone photoreceptors. Cone function and day vision were restored for at least 33 months in two young specimens. The therapy was less efficient for older dogs.[80]

In September it was announced that an 18-year-old male patient in France with beta-thalassemia major had been successfully treated.[81] Beta-thalassemia major is an inherited blood disease in which beta haemoglobin is missing and patients are dependent on regular lifelong blood transfusions.[82] The technique used a lentiviral vector to transduce the human -globin gene into purified blood and marrow cells obtained from the patient in June 2007.[83] The patient's haemoglobin levels were stable at 9 to 10 g/dL. About a third of the hemoglobin contained the form introduced by the viral vector and blood transfusions were not needed.[83][84] Further clinical trials were planned.[85]Bone marrow transplants are the only cure for thalassemia, but 75% of patients do not find a matching donor.[84]

Cancer immunogene therapy using modified anti gene, antisense / triple helix approach was introduced in South America in 2010/11 in La Sabana University, Bogota (Ethical Committee 14.12.2010, no P-004-10). Considering the ethical aspect of gene diagnostic and gene therapy targeting IGF-I, the IGF-I expressing tumors i.e. lung and epidermis cancers, were treated (Trojan et al. 2016). [86][87]

In 2007 and 2008, a man was cured of HIV by repeated Hematopoietic stem cell transplantation (see also Allogeneic stem cell transplantation, Allogeneic bone marrow transplantation, Allotransplantation) with double-delta-32 mutation which disables the CCR5 receptor. This cure was accepted by the medical community in 2011.[88] It required complete ablation of existing bone marrow, which is very debilitating.

In August two of three subjects of a pilot study were confirmed to have been cured from chronic lymphocytic leukemia (CLL). The therapy used genetically modified T cells to attack cells that expressed the CD19 protein to fight the disease.[21] In 2013, the researchers announced that 26 of 59 patients had achieved complete remission and the original patient had remained tumor-free.[89]

Human HGF plasmid DNA therapy of cardiomyocytes is being examined as a potential treatment for coronary artery disease as well as treatment for the damage that occurs to the heart after myocardial infarction.[90][91]

In 2011 Neovasculgen was registered in Russia as the first-in-class gene-therapy drug for treatment of peripheral artery disease, including critical limb ischemia; it delivers the gene encoding for VEGF.[92][27] Neovasculogen is a plasmid encoding the CMV promoter and the 165 amino acid form of VEGF.[93][94]

The FDA approved Phase 1 clinical trials on thalassemia major patients in the US for 10 participants in July.[95] The study was expected to continue until 2015.[96]

In July 2012, the European Medicines Agency recommended approval of a gene therapy treatment for the first time in either Europe or the United States. The treatment used Alipogene tiparvovec (Glybera) to compensate for lipoprotein lipase deficiency, which can cause severe pancreatitis.[97] The recommendation was endorsed by the European Commission in November 2012[11][28][98][99] and commercial rollout began in late 2014.[100]

In December 2012, it was reported that 10 of 13 patients with multiple myeloma were in remission "or very close to it" three months after being injected with a treatment involving genetically engineered T cells to target proteins NY-ESO-1 and LAGE-1, which exist only on cancerous myeloma cells.[23]

In March researchers reported that three of five subjects who had acute lymphocytic leukemia (ALL) had been in remission for five months to two years after being treated with genetically modified T cells which attacked cells with CD19 genes on their surface, i.e. all B-cells, cancerous or not. The researchers believed that the patients' immune systems would make normal T-cells and B-cells after a couple of months. They were also given bone marrow. One patient relapsed and died and one died of a blood clot unrelated to the disease.[22]

Following encouraging Phase 1 trials, in April, researchers announced they were starting Phase 2 clinical trials (called CUPID2 and SERCA-LVAD) on 250 patients[101] at several hospitals to combat heart disease. The therapy was designed to increase the levels of SERCA2, a protein in heart muscles, improving muscle function.[102] The FDA granted this a Breakthrough Therapy Designation to accelerate the trial and approval process.[103] In 2016 it was reported that no improvement was found from the CUPID 2 trial.[104]

In July researchers reported promising results for six children with two severe hereditary diseases had been treated with a partially deactivated lentivirus to replace a faulty gene and after 732 months. Three of the children had metachromatic leukodystrophy, which causes children to lose cognitive and motor skills.[105] The other children had Wiskott-Aldrich syndrome, which leaves them to open to infection, autoimmune diseases and cancer.[106] Follow up trials with gene therapy on another six children with Wiskott-Aldrich syndrome were also reported as promising.[107][108]

In October researchers reported that two children born with adenosine deaminase severe combined immunodeficiency disease (ADA-SCID) had been treated with genetically engineered stem cells 18 months previously and that their immune systems were showing signs of full recovery. Another three children were making progress.[19] In 2014 a further 18 children with ADA-SCID were cured by gene therapy.[109] ADA-SCID children have no functioning immune system and are sometimes known as "bubble children."[19]

Also in October researchers reported that they had treated six haemophilia sufferers in early 2011 using an adeno-associated virus. Over two years later all six were producing clotting factor.[19][110]

Data from three trials on Topical cystic fibrosis transmembrane conductance regulator gene therapy were reported to not support its clinical use as a mist inhaled into the lungs to treat cystic fibrosis patients with lung infections.[111]

In January researchers reported that six choroideremia patients had been treated with adeno-associated virus with a copy of REP1. Over a six-month to two-year period all had improved their sight.[112][113] By 2016, 32 patients had been treated with positive results and researchers were hopeful the treatment would be long-lasting.[16] Choroideremia is an inherited genetic eye disease with no approved treatment, leading to loss of sight.

In March researchers reported that 12 HIV patients had been treated since 2009 in a trial with a genetically engineered virus with a rare mutation (CCR5 deficiency) known to protect against HIV with promising results.[114][115]

Clinical trials of gene therapy for sickle cell disease were started in 2014[116][117] although one review failed to find any such trials.[118]

In February LentiGlobin BB305, a gene therapy treatment undergoing clinical trials for treatment of beta thalassemia gained FDA "breakthrough" status after several patients were able to forgo the frequent blood transfusions usually required to treat the disease.[119]

In March researchers delivered a recombinant gene encoding a broadly neutralizing antibody into monkeys infected with simian HIV; the monkeys' cells produced the antibody, which cleared them of HIV. The technique is named immunoprophylaxis by gene transfer (IGT). Animal tests for antibodies to ebola, malaria, influenza and hepatitis are underway.[120][121]

In March scientists, including an inventor of CRISPR, urged a worldwide moratorium on germline gene therapy, writing scientists should avoid even attempting, in lax jurisdictions, germline genome modification for clinical application in humans until the full implications are discussed among scientific and governmental organizations.[122][123][124][125]

Also in 2015 Glybera was approved for the German market.[126]

In October, researchers announced that they had treated a baby girl, Layla Richards, with an experimental treatment using donor T-cells genetically engineered to attack cancer cells. Two months after the treatment she was still free of her cancer (a highly aggressive form of acute lymphoblastic leukaemia [ALL]). Children with highly aggressive ALL normally have a very poor prognosis and Layla's disease had been regarded as terminal before the treatment.[127]

In December, scientists of major world academies called for a moratorium on inheritable human genome edits, including those related to CRISPR-Cas9 technologies[128] but that basic research including embryo gene editing should continue.[129]

In April the Committee for Medicinal Products for Human Use of the European Medicines Agency endorsed a gene therapy treatment called Strimvelis and recommended it be approved.[130][131] This treats children born with ADA-SCID and who have no functioning immune system - sometimes called the "bubble baby" disease. This would be the second gene therapy treatment to be approved in Europe.[132]

Speculated uses for gene therapy include:

Gene Therapy techniques have the potential to provide alternative treatments for those with infertility. Recently, successful experimentation on mice has proven that fertility can be restored by using the gene therapy method, CRISPR.[133] Spermatogenical stem cells from another organism were transplanted into the testes of an infertile male mouse. The stem cells re-established spermatogenesis and fertility.[134]

Athletes might adopt gene therapy technologies to improve their performance.[135]Gene doping is not known to occur, but multiple gene therapies may have such effects. Kayser et al. argue that gene doping could level the playing field if all athletes receive equal access. Critics claim that any therapeutic intervention for non-therapeutic/enhancement purposes compromises the ethical foundations of medicine and sports.[136]

Genetic engineering could be used to change physical appearance, metabolism, and even improve physical capabilities and mental faculties such as memory and intelligence. Ethical claims about germline engineering include beliefs that every fetus has a right to remain genetically unmodified, that parents hold the right to genetically modify their offspring, and that every child has the right to be born free of preventable diseases.[137][138][139] For adults, genetic engineering could be seen as another enhancement technique to add to diet, exercise, education, cosmetics and plastic surgery.[140][141] Another theorist claims that moral concerns limit but do not prohibit germline engineering.[142]

Possible regulatory schemes include a complete ban, provision to everyone, or professional self-regulation. The American Medical Associations Council on Ethical and Judicial Affairs stated that "genetic interventions to enhance traits should be considered permissible only in severely restricted situations: (1) clear and meaningful benefits to the fetus or child; (2) no trade-off with other characteristics or traits; and (3) equal access to the genetic technology, irrespective of income or other socioeconomic characteristics."[143]

As early in the history of biotechnology as 1990, there have been scientists opposed to attempts to modify the human germline using these new tools,[144] and such concerns have continued as technology progressed.[145] With the advent of new techniques like CRISPR, in March 2015 a group of scientists urged a worldwide moratorium on clinical use of gene editing technologies to edit the human genome in a way that can be inherited.[122][123][124][125] In April 2015, researchers sparked controversy when they reported results of basic research to edit the DNA of non-viable human embryos using CRISPR.[133][146]

Regulations covering genetic modification are part of general guidelines about human-involved biomedical research.

The Helsinki Declaration (Ethical Principles for Medical Research Involving Human Subjects) was amended by the World Medical Association's General Assembly in 2008. This document provides principles physicians and researchers must consider when involving humans as research subjects. The Statement on Gene Therapy Research initiated by the Human Genome Organization (HUGO) in 2001 provides a legal baseline for all countries. HUGOs document emphasizes human freedom and adherence to human rights, and offers recommendations for somatic gene therapy, including the importance of recognizing public concerns about such research.[147]

No federal legislation lays out protocols or restrictions about human genetic engineering. This subject is governed by overlapping regulations from local and federal agencies, including the Department of Health and Human Services, the FDA and NIH's Recombinant DNA Advisory Committee. Researchers seeking federal funds for an investigational new drug application, (commonly the case for somatic human genetic engineering), must obey international and federal guidelines for the protection of human subjects.[148]

NIH serves as the main gene therapy regulator for federally funded research. Privately funded research is advised to follow these regulations. NIH provides funding for research that develops or enhances genetic engineering techniques and to evaluate the ethics and quality in current research. The NIH maintains a mandatory registry of human genetic engineering research protocols that includes all federally funded projects.

An NIH advisory committee published a set of guidelines on gene manipulation.[149] The guidelines discuss lab safety as well as human test subjects and various experimental types that involve genetic changes. Several sections specifically pertain to human genetic engineering, including Section III-C-1. This section describes required review processes and other aspects when seeking approval to begin clinical research involving genetic transfer into a human patient.[150] The protocol for a gene therapy clinical trial must be approved by the NIH's Recombinant DNA Advisory Committee prior to any clinical trial beginning; this is different from any other kind of clinical trial.[149]

As with other kinds of drugs, the FDA regulates the quality and safety of gene therapy products and supervises how these products are used clinically. Therapeutic alteration of the human genome falls under the same regulatory requirements as any other medical treatment. Research involving human subjects, such as clinical trials, must be reviewed and approved by the FDA and an Institutional Review Board.[151][152]

Gene therapy is the basis for the plotline of the film I Am Legend[153] and the TV show Will Gene Therapy Change the Human Race?.[154]

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Entertainment - CBC News

This type of therapy is called therapeutic gene therapy or the use of genes as medicine. It is an experimental form of treatment that is still being developed, but it has the potential to revolutionise treatment for all kinds of genetic conditions.

Gene therapy targets the faulty genes responsible for genetic diseases. Inheriting a faulty (mutated) gene can directly cause a wide range of disorders such as cystic fibrosis and haemophilia. It can also cause susceptibility to some cancers. Gene therapy can be used to replace a faulty gene with a healthy version or to introduce a new gene that can cure a condition or modify its effects. This type of gene therapy is called therapeutic gene therapy or the use of genes as medicine. It is an experimental form of treatment that is still in its infancy but has the potential to revolutionise treatment for all kinds of genetic diseases.

Inheriting one or both copies of a faulty gene can cause a wide range of conditions such as haemophilia and cystic fibrosis, and can also result in increased susceptibility to some cancers. Gene therapy targets the faulty genes responsible for a genetic condition. Gene therapy can be used to replace a faulty gene copy with a working version or to introduce a new gene that can cure a condition or modify its effects.

One promising technique is to put the working gene inside a harmless virus, which has had most of its own genes removed it has been deactivated. A virus that causes disease (such as the common cold) works by slipping into a cell, taking over its DNA and forcing it to produce more viruses. Similarly, a deactivated virus can enter the specific cell and deliver the working gene.

Other techniques involve using stem cells. These are immature cells that have the potential to develop into cells with different functions. In this technique, stem cells are manipulated in the laboratory to accept new genes that can then change their behaviour. For example, a gene might be inserted into a stem cell that could make it better able to survive chemotherapy. This would be of assistance to those patients who could benefit from further chemotherapy following stem cell transplantation.

To make sure that future generations of the persons family were not affected by the genetic condition, their germ cells would need to undergo gene therapy too. However, a complicated range of ethical issues, as well as technical problems, means that gene therapy of germ cells is only a remote possibility.

The majority of trials are being conducted in the US and Europe, with only a modest number initiated in other countries, including Australia (1.6%). Most trials focus on treating acquired conditions such as cancer and AIDS, although an increasing number of genetic conditions are being targeted.

The concern is that manipulating factors such as intelligence might be tried, once gene therapy becomes commonplace. Ordinary characteristics, such as shortness or average IQ, might then be considered subnormal.

Another concern is that gene therapy might only be available to the rich. The challenge for nations experimenting with gene therapy is to come up with workable, fair and ethical guidelines for its use.

This page has been produced in consultation with and approved by: Better Health Channel - (need new cp)

Last updated: May 2011

Content on this website is provided for education and information purposes only. Information about a therapy, service, product or treatment does not imply endorsement and is not intended to replace advice from your doctor or other registered health professional. Content has been prepared for Victorian residents and wider Australian audiences, and was accurate at the time of publication. Readers should note that, over time, currency and completeness of the information may change. All users are urged to always seek advice from a registered health care professional for diagnosis and answers to their medical questions.

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Gene therapy - Better Health Channel

Gene therapy is using "genes as medicine". It is an experimental approach to treating genetic disease where the faulty gene is fixed, replaced or supplemented with a healthy gene so that it can function normally. Most genetic diseases cannot be treated, but gene therapy research gives some hope to patients and their families as a possible cure. However, this technology does not come without risks and many clinical trials to evaluate its effectiveness need to be done before gene therapy can be put to regular medical use.

To get a new gene into a cell's genome, it must be carried in a molecule called a vector. The most common vectors currently being used are viruses, which naturally invade cells and insert their genetic material into that cell's genome. To use a virus as a vector, the virus' own genes are removed and replaced with the new gene destined for the cell. When the virus attacks the cell, it will insert the genetic material it carries. A successful transfer will result in the target cell now carrying the new gene that will correct the problem caused by the faulty gene.

Viruses that can be used as vectors include retroviruses like HIV, adenoviruses (one of which causes the common cold), adeno-associated viruses and herpes simplex viruses. There are also many non-viral vectors being tested for gene therapy uses. These include artificial lipid spheres called liposomes, DNA attached to a molecule that will bind to a receptor on the target cell, artificial chromosomes and naked DNA that is not attached to another molecule at all and can be directly inserted into the cell.

The actual transfer of the new gene into the target cell can happen in two ways: ex vivo and in vivo. The ex vivo approach involves transferring the new gene into cells that have been removed from the patient and grown in the laboratory. Once the transfer is complete, the cells are returned to the patient, where they will continue to grow and produce the new gene product. The in vivo approach delivers the vector directly to the patient, where transfer of the new gene will occur in the target cells within the body.

Conditions or disorders that result from mutations in a single gene are potentially the best candidates for gene therapy. However, the many challenges met by researchers working on gene therapy mean that its application is still limited while the procedure is being perfected.

Before gene therapy can be used to treat a certain genetic condition or disorder, certain requirements need to be met:

Clinical trials for gene therapy in other countries (for example France and the United Kingdom) have shown that there are still several major factors preventing gene therapy from becoming a routine way to treat genetic conditions and disorders. While the transfer of the new gene into the target cells has worked, it does not seem to have a long-lasting effect. This suggests that patients would have to be treated multiple times to control the condition or disorder. There is also always a risk of a severe immune response, since the immune cells are trained to attack any foreign molecule in the body. Working with viral vectors has proven to be challenging because they are difficult to control and the body immediately recognizes and attacks common viruses. Recent work has focussed on potential non-viral vectors to avoid the complications associated with the viral vectors. Finally, while there are thousands of single-gene disorders, the more common genetic disorders are actually caused by multiple genes, which do not make them good candidates for gene therapy.

One promising application of gene therapy is in treating type I diabetes. Researchers in the United States used an adenovirus as a vector to deliver the gene for hepatocyte growth factor (HGF) to pancreatic islet cells removed from rats. They injected the altered cells into diabetic rats and, within a day, the rats were controlling their blood glucose levels better than the control rats. This model mimics the transplantation of islet cells in humans and shows that the addition of the HGF gene greatly enhances the islet cells' function and survival.

In Canada, researchers in Edmonton, Alberta also developed a protocol to treat type I diabetes. Doctors use ultrasound to guide a small catheter through the upper abdomen and into the liver. Pancreatic islet cells are then injected through the catheter into the liver. In time, islets are established in the liver and begin releasing insulin.

Another application for gene therapy is in treating X-linked severe combined immunodeficiency (X-SCID), a disease where a baby lacks both T and B cells of the immune system and is vulnerable to infections. The current treatment is bone marrow transplant from a matched sibling, which is not always possible or effective in the long term. Researchers in France and the United Kingdom, knowing the disease was caused by a faulty gene on the X chromosome, treated 14 children by replacing the faulty gene ex vivo. Upon receiving the altered cells, the patients showed great improvements in their immune system functions. Unfortunately, two of the children developed a form of leukemia several years after the treatment. Further investigation showed that the vector had inserted the gene near a proto-oncogene, which led to uncontrolled growth of the T cells. The clinical trials were put on hold until a safer method can be designed and tested.

Excerpt from:
Gene Therapy - Biotechnology - Science and Research

Gene Therapy for Diseases

Gene Therapy has made important medical advances in less than two decades. Within this short time span, it has moved from the conceptual stage to technology development and laboratory research to clinical translational trials for a variety of deadly diseases. Among the most notable advancements are the following:

Severe Combined Immune Deficiency (ADA-SCID) ADA-SCID is also known as the bubble boy disease. Affected children are born without an effective immune system and will succumb to infections outside of the bubble without bone marrow transplantation from matched donors. A landmark study representing a first case of gene therapy "cure," or at least a long-term correction, for patients with deadly genetic disorder was conducted by investigators in Italy. The therapeutic gene called ADA was introduced into the bone marrow cells of such patients in the laboratory, followed by transplantation of the genetically corrected cells back to the same patients. The immune system was reconstituted in all six treated patients without noticeable side effects, who now live normal lives with their families without the need for further treatment.

Chronic Granulomatus Disorder (CGD) CGD is a genetic disease in the immune system that leads to the patients' inability to fight off bacterial and fungal infections that can be fatal. Using similar technologies as in the ADA-SCID trial, investigators in Germany treated two patients with this disease, whose reconstituted immune systems have since been able to provide them with full protection against microbial infections for at least two years.

Hemophilia Patients born with Hemophilia are not able to induce blood clots and suffer from external and internal bleeding that can be life threatening. In a clinical trial conducted in the United States , the therapeutic gene was introduced into the liver of patients, who then acquired the ability to have normal blood clotting time. The therapeutic effect however, was transient because the genetically corrected liver cells were recognized as foreign and rejected by the healthy immune system in the patients. This is the same problem faced by patients after organ transplantation, and curative outcome by gene therapy might be achievable with immune-suppression or alternative gene delivery strategies currently being tested in preclinical animal models of this disease.

Other genetic disorders After many years of laboratory and preclinical research in appropriate animal models of disease, a number of clinical trials will soon be launched for various genetic disorders that include congenital blindness, lysosomal storage disease and muscular dystrophy, among others.

Cancer Multiple gene therapy strategies have been developed to treat a wide variety of cancers, including suicide gene therapy, oncolytic virotherapy, anti-angiogenesis and therapeutic gene vaccines. Two-thirds of all gene therapy trials are for cancer and many of these are entering the advanced stage, including a Phase III trial of Ad.p53 for head and neck cancer and two different Phase III gene vaccine trials for prostate cancer and pancreas cancer. Additionally, numerous Phase I and Phase II clinical trials for cancers in the brain, skin, liver, colon, breast and kidney among others, are being conducted in academic medical centers and biotechnology companies, using novel technologies and therapeutics developed on-site.

Neurodegenerative Diseases Recent progress in gene therapy has allowed for novel treatments of neurodegenerative diseases such as Parkinson's Disease and Huntington's Disease, for which exciting treatment results have been obtained in appropriate animal models of the corresponding human diseases. Phase I clinical trials for these neurodegenerative disorders have been, or will soon be, launched.

Other acquired diseases The same gene therapeutic techniques have been applied to treat other acquired disorders such as viral infections (e.g. influenza, HIV, hepatitis), heart disease and diabetes, among others. Some of these have entered, or will soon be entering, into early phase clinical trials.

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Gene Therapy for Diseases | ASGCT - American Society of Gene & Cell Therapy

Gene Eliza Tierney (November 19, 1920 November 6, 1991)[3] was an American film and stage actress. Acclaimed as a great beauty, she became established as a leading lady.[4][5] Tierney was best known for her portrayal of the title character in the film Laura (1944), and was nominated for an Academy Award for Best Actress for her performance as Ellen Berent Harland in Leave Her to Heaven (1945).[6]

Tierney's other roles include Martha Strable Van Cleve in Heaven Can Wait (1943), Isabel Bradley Maturin in The Razor's Edge (1946), Lucy Muir in The Ghost and Mrs. Muir (1947), Ann Sutton in Whirlpool (1949), Maggie Carleton McNulty in The Mating Season (1951), and Anne Scott in The Left Hand of God (1955).

Tierney was born on November 19, 1920 in Brooklyn, New York, the daughter of Howard Sherwood Tierney and Belle Lavina Taylor. The family owned a brownstone at 900 St. Mark's Avenue, which was at the time a very fashionable street in the Crown Heights neighborhood of Brooklyn. She was named after a beloved uncle, who died young.[6][pageneeded] She had an elder brother, Howard Sherwood Butch Tierney, Jr., and a younger sister, Patricia Pat Tierney. Their father was a successful insurance broker of Irish descent, their mother a former physical education instructor.[6][pageneeded]

Tierney attended St. Margaret's School in Waterbury, Connecticut, and the Unquowa School in Fairfield. She published her first poem, entitled "Night", in the school magazine and wrote poetry occasionally throughout her life. Tierney played Jo in a student production of Little Women, based on the novel by Louisa May Alcott.

Tierney spent two years in Europe, attending Brillantmont International School in Lausanne, Switzerland, where she learned to speak fluent French. She returned to the U.S. in 1938 and attended Miss Porter's School in Farmington, Connecticut . On a family trip to the West Coast, she visited Warner Bros. studios, where a cousin worked as a producer of historical short films. director Anatole Litvak, taken by the 17-year-olds beauty, told her that she should become an actress. Warner Bros. wanted to sign her to a contract, but her parents advised against it because of the relatively low salary; they also wanted her in a higher social position.[6][pageneeded]

Tierney's society debut occurred on September 24, 1938, when she was 17 years old.[6][pageneeded] Soon bored with society life, she decided to pursue an acting career. Her father said, If Gene is to be an actress, it should be in the legitimate theatre.[7] Tierney studied acting at a small Greenwich Village acting studio in New York with Broadway director and actor Benno Schneider. She became a protge of Broadway producer-director George Abbott.[7][8]

In Tierney's first role on Broadway, she carried a bucket of water across the stage in What a Life! (1938). A Variety magazine critic declared, "Miss Tierney is certainly the most beautiful water carrier I've ever seen!" She also worked as an understudy in The Primrose Path (1938).

The following year, she appeared in the role of Molly O'Day in the Broadway production Mrs. O'Brien Entertains (1939).[6][pageneeded] The New York Times critic Brooks Atkinson wrote, "As an Irish maiden fresh from the old country, Gene Tierney in her first stage performance is very pretty and refreshingly modest."[6][pageneeded] That same year, Tierney appeared as Peggy Carr in Ring Two (1939) to favorable reviews. Theater critic Richard Watts, Jr. of the New York Herald Tribune wrote, "I see no reason why Miss Tierney should not have an interesting theatrical career that is, if cinema does not kidnap her away."[6][pageneeded]

Tierney's father set up a corporation, Belle-Tier, to fund and promote her acting career. Columbia Pictures signed her to a six-month contract in 1939. She met Howard Hughes, who tried unsuccessfully to seduce her. From a well-to-do family herself, she was not impressed by his wealth.[6][pageneeded] Hughes eventually became a lifelong friend.

After a cameraman advised Tierney to lose a little weight, she wrote Harper's Bazaar magazine for a diet, which she followed for the next 25 years. Tierney was initially offered the lead role in National Velvet, but production was delayed.[6][pageneeded] When Columbia Pictures failed to find Tierney a project, she returned to Broadway and starred as Patricia Stanley to critical and commercial success in The Male Animal (1940). In The New York Times, Brooks Atkinson wrote, "Tierney blazes with animation in the best performance she has yet given".[6][pageneeded] She was the toast of Broadway before her 20th birthday. The Male Animal was a hit, and Tierney was featured in Life magazine. She was also photographed by Harper's Bazaar, Vogue, and Collier's Weekly.[6][pageneeded]

Two weeks after The Male Animal opened, Darryl F. Zanuck, the head of 20th Century Fox, was rumored to have been in the audience. During the performance, he told an assistant to note Tierney's name. Later that night, Zanuck dropped by the Stork Club, where he saw a young lady on the dance floor. He told his assistant, "Forget the girl from the play. See if you can sign that one." It was Tierney. At first, Zanuck did not think she was the actress he had seen. Tierney was quoted (after the fact), saying: "I always had several different 'looks', a quality that proved useful in my career."[6][pageneeded][8]

Tierney signed with 20th Century-Fox[6][pageneeded] and her motion picture debut was in a supporting role as Eleanor Stone in Fritz Lang's western The Return of Frank James (1940), opposite Henry Fonda.

A small role as Barbara Hall followed in Hudson's Bay (1941) with Paul Muni and she co-starred as Ellie Mae Lester in John Ford's comedy Tobacco Road (also 1941), and played the title role in Belle Starr, Zia in Sundown, and Victoria Charteris (Poppy Smith) in The Shanghai Gesture. She played Eve in Son of Fury: The Story of Benjamin Blake (1942), as well as the dual role of Susan Miller (Linda Worthington) in Rouben Mamoulian's screwball comedy Rings on Her Fingers, and roles as Kay Saunders in Thunder Birds, and Miss Young in China Girl (all 1942).[citation needed]

Receiving top billing in Ernst Lubitsch's comedy Heaven Can Wait (1943), as Martha Strable Van Cleve, signaled an upward turn in Tierney's career. Tierney recalled during the production of Heaven Can Wait:

"Lubitsch was a tyrant on the set, the most demanding of directors. After one scene, which took from noon until five to get, I was almost in tears from listening to Lubitsch shout at me. The next day I sought him out, looked him in the eye, and said, 'Mr. Lubitsch, I'm willing to do my best but I just can't go on working on this picture if you're going to keep shouting at me.' 'I'm paid to shout at you', he bellowed. 'Yes', I said, 'and I'm paid to take it but not enough.' After a tense pause, Lubitsch broke out laughing. From then on we got along famously."[6][pageneeded]

Tierney starred in what became her best remembered role: the title role in Otto Preminger's film noir Laura (1944), opposite Dana Andrews. After playing Tina Tomasino in A Bell for Adano (1945), she played the jealous, narcissistic femme fatale Ellen Berent Harland in Leave Her to Heaven (1945), adapted from a best selling novel by Ben Ames Williams. Appearing with Cornel Wilde, Tierney won an Academy Award nomination for Best Actress. This was 20th Century-Fox' most successful film of the 1940s. It was cited by director Martin Scorsese as one of his favorite films of all time, and he assessed Tierney as one of the most underrated actresses of the Golden Era.[9]

Tierney then starred as Miranda Wells in Dragonwyck (1946), along with Walter Huston and Vincent Price. It was Joseph L. Mankiewicz' debut film as a director, In the same period, she starred as Isabel Bradley, opposite Tyrone Power, in The Razor's Edge (also 1946), an adaptation of W. Somerset Maugham's novel of the same name. Her performance was critically praised.[citation needed]

Tierney played Lucy Muir in Mankiewicz's The Ghost and Mrs. Muir (1947), opposite Rex Harrison.[10] The following year, she co-starred again with Power, this time as Sara Farley in the successful screwball comedy That Wonderful Urge (1948). As the decade came to a close, Tierney reunited with Laura director Preminger to star as Ann Sutton in the classic film noir Whirlpool (1949), co-starring Richard Conte and Jos Ferrer. She appeared in two other film noirs: Jules Dassin's Night and the City, shot in London, and Otto Preminger's Where the Sidewalk Ends (both 1950).[citation needed]

Tierney was loaned to Paramount Pictures, giving a comic turn as Maggie Carleton in Mitchell Leisen's ensemble farce, The Mating Season (1951), with John Lund, Thelma Ritter, and Miriam Hopkins.[6][pageneeded] She gave a tender performance as Midge Sheridan in the Warner Bros. film, Close to My Heart (1951), with Ray Milland. The film is about a couple trying to adopt a child.[6][pageneeded] Later in her career, she was reunited with Milland in Daughter of the Mind (1969).

After Tierney appeared opposite Rory Calhoun as Teresa in Way of a Gaucho (1952), her contract at 20th Century-Fox expired. That same year, she starred as Dorothy Bradford in Plymouth Adventure, opposite Spencer Tracy at MGM. She and Tracy had a brief affair during this time.[11] Tierney played Marya Lamarkina opposite Clark Gable in Never Let Me Go (1953), filmed in England.[6][pageneeded]

Tierney remained in Europe to play Kay Barlow in United Artists' Personal Affair (1953). While in Europe, she began a romance with Prince Aly Khan, but their marriage plans met with fierce opposition from his father Aga Khan III.[12] Early in 1953, Tierney returned to the U.S. to co-star in film noir Black Widow (1954) as Iris Denver, with Ginger Rogers and Van Heflin.

Tierney had reportedly started smoking after a screening of her first movie to lower her voice, because she felt, "Isound like an angry Minnie Mouse."[13] She subsequently became a heavy smoker.[13]

With difficult events in her personal life, Tierney struggled for years with episodes of manic depression. In 1943, she gave birth to a daughter, Daria, who was deaf and mentally disabled, the result of a fan breaking out of rubella quarantine and infecting the pregnant Tierney while she volunteered at the Hollywood Canteen. In 1953, she suffered problems with concentration, which affected her film appearances. She dropped out of Mogambo and was replaced by Grace Kelly.[6][pageneeded] While playing Anne Scott in The Left Hand of God (1955), opposite Humphrey Bogart, Tierney became ill. Bogart had a personal experience as he was close to a sister who suffered from mental illness, so during the production, he fed Tierney her lines and encouraged her to seek help.[6][pageneeded]

Tierney consulted a psychiatrist and was admitted to Harkness Pavilion in New York. Later, she went to the Institute of Living in Hartford, Connecticut. After some 27 shock treatments, intended to alleviate severe depression, Tierney fled the facility, but was caught and returned. She later became an outspoken opponent of shock treatment therapy, claiming it had destroyed significant portions of her memory.[citation needed]

In late December 1957, Tierney, from her mother's apartment in Manhattan, stepped onto a ledge 14 stories above ground and remained for about 20 minutes in what was considered a suicide attempt.[14] Police were called, and afterwards Tierney's family arranged for her to be admitted to the Menninger Clinic in Topeka, Kansas. The following year, after treatment for depression, she was released. Afterwards, she worked as a sales girl in a local dress shop with hopes of integrating back into society,[14] but she was recognized by a customer, resulting in sensational newspaper headlines.

Later in 1958, 20th Century-Fox offered Tierney a lead role in Holiday for Lovers (1959), but the stress upon her proved too great, so only days into production, she dropped out of the film and returned to Menninger for a time.[14]

Tierney made a screen comeback in Advise and Consent (1962), co-starring with Franchot Tone.[6][pageneeded] Soon afterwards, she played Albertine Prine in Toys in the Attic (1963), based on the play by Lillian Hellman. This was followed by the international production of Las cuatro noches de la luna llena, (Four Nights of the Full Moon - 1963), in which she starred with Dan Dailey. She received critical praise overall for her performances.[citation needed]

Tierney's career as a solid character actress seemed to be back on track as she played Jane Barton in The Pleasure Seekers (1964), but then she suddenly retired. She returned to star in the television movie Daughter of the Mind (1969) with Don Murray and Ray Milland. Her final performance was in the TV miniseries Scruples (1980).[6][pageneeded]

Tierney married two men: the first was Oleg Cassini, a costume and fashion designer, on June 1, 1941, with whom she eloped. Her parents opposed the marriage, as he was from a Russian-Italian family and born in France.[14] She had two daughters, Antoinette Daria Cassini (October 15, 1943 September 11, 2010)[15] and Christina "Tina" Cassini (November 19, 1948 March 31, 2015), born after their divorce, paternity of whom was the subject of intrigue and speculation at the time due to Tierney's links with Howard Hughes, Tyrone Power, John Fitzgerald Kennedy, and Charles Feldman.[16]

In June 1943, while pregnant with Daria, Tierney contracted rubella (German measles), likely from a fan ill with the disease.[14] Daria was born prematurely in Washington, DC, weighing three pounds, two ounces (1.42kg) and requiring a total blood transfusion. The rubella caused congenital damage: Daria was deaf, partially blind with cataracts, and severely mentally disabled. She was institutionalized for much of her life.[14] This was partial inspiration for the Agatha Christie novel The Mirror Crack'd from Side to Side.

Tierney's friend Howard Hughes paid for Daria's medical expenses, ensuring the girl received the best care. Tierney never forgot his acts of kindness.[6]

Tierney and Cassini separated October 20, 1946, and entered into a property settlement agreement November 10, 1946.[17] Periodicals during this period record Tierney with Charles K. Feldman,[18] including articles related to her "twosoming" with Feldman, her "current best beau".[19] An uncontested divorce followed in California; their final divorce decree was dated March 13, 1948. The Los Angeles Times reported that the couple reconciled on April 19, 1948, but did not remarry.[17]

During their separation, Tierney met John F. Kennedy, a young World War II veteran, who was visiting the set of Dragonwyck in 1946. They began a romance that she ended the following year after Kennedy told her he could never marry her because of his political ambitions.[11] In 1960, Tierney sent Kennedy a note of congratulations on his victory in the presidential election. During this time, newspapers documented Tierney's other romantic relationships, including Kirk Douglas.[20]

While filming for Personal Affair in Europe, she began a romance with Prince Aly Khan.[12] They became engaged in 1952, while Khan was going through a divorce from Rita Hayworth.[21] Their marriage plans, however, met with fierce opposition from his father, Aga Khan III.[12]

Cassini later bequeathed $500,000 in trust to Daria and $1,000,000 to Christina.[22][23] Cassini and Tierney remained friends until her death in November 1991.

In 1958, Tierney met Texas oil baron W. Howard Lee, who had been married to actress Hedy Lamarr since 1953. Lee and Lamarr divorced in 1960 after a long battle over alimony,[24] then Lee and Tierney married in Aspen, Colorado, on July 11, 1960. They lived quietly in Houston, Texas, and Florida[14] until his death in 1981.[24]

In 1960, 20th Century Fox announced Tierney would play the lead role in Return to Peyton Place, but she dropped out of the project after becoming pregnant. She later miscarried.[6][pageneeded]

Tierney's autobiography, Self-Portrait, in which she candidly discusses her life, career, and mental illness, was published in 1979.

Tierney's second husband, W. Howard Lee, died on February 17, 1981 after a long illness.[24]

In 1986, Tierney was honored alongside actor Gregory Peck with the first Donostia Lifetime Achievement Award at the San Sebastian Film Festival in Spain.[25]

Tierney has a star on the Hollywood Walk of Fame at 6125 Hollywood Boulevard.

Tierney died of emphysema on November 6, 1991 in Houston, thirteen days before her 71st birthday.[3] She is interred in Glenwood Cemetery in Houston. Tierney was survived by her daughters Daria and Christina. Certain documents of Tierney's film-related material, personal papers, letters, etc., are held in the Wesleyan University Cinema Archives, to which scholars, media experts, and the public may have access.[26]

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Gene Tierney - Wikipedia, the free encyclopedia

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Cell Cycle, organism-specific biosystem Cell Cycle

Cell Cycle Checkpoints, organism-specific biosystemA hallmark of the human cell cycle in normal somatic cells is its precision. This remarkable fidelity is achieved by a number of signal transduction pathways, known as checkpoints, which monitor cell...

Cell Cycle, Mitotic, organism-specific biosystemThe replication of the genome and the subsequent segregation of chromosomes into daughter cells are controlled by a series of events collectively known as the cell cycle. DNA replication is carried o...

Cell cycle, organism-specific biosystemThe cell cycle is the series of events that takes place in a cell leading to its division and duplication (replication). Regulation of the cell cycle involves processes crucial to the survival of a c...

Cell cycle, organism-specific biosystemMitotic cell cycle progression is accomplished through a reproducible sequence of events, DNA replication (S phase) and mitosis (M phase) separated temporally by gaps known as G1 and G2 phases. Cycli...

Cell cycle, conserved biosystemMitotic cell cycle progression is accomplished through a reproducible sequence of events, DNA replication (S phase) and mitosis (M phase) separated temporally by gaps known as G1 and G2 phases. Cycli...

Cellular Senescence, organism-specific biosystemCellular senescence involves irreversible growth arrest accompanied by phenotypic changes such as enlarged morphology, reorganization of chromatin through formation of senescence-associated heterochr...

Cellular responses to stress, organism-specific biosystemCells are subject to external molecular and physical stresses such as foreign molecules that perturb metabolic or signaling processes, and changes in temperature or pH. The ability of cells and tissu...

Central carbon metabolism in cancer, organism-specific biosystemMalignant transformation of cells requires specific adaptations of cellular metabolism to support growth and survival. In the early twentieth century, Otto Warburg established that there are fundamen...

Central carbon metabolism in cancer, conserved biosystemMalignant transformation of cells requires specific adaptations of cellular metabolism to support growth and survival. In the early twentieth century, Otto Warburg established that there are fundamen...

Chaperonin-mediated protein folding, organism-specific biosystemThe eukaryotic chaperonin TCP-1 ring complex (TRiC/ CCT) plays an essential role in the folding of a subset of proteins prominent among which are the actins and tubulins (reviewed in Altschuler and...

Chronic myeloid leukemia, organism-specific biosystemChronic myelogenous leukemia (CML) originates in a pluripotent hematopoetic stem cell of the bone marrow and is characterized by greatly increased numbers of granulocytes in the blood. Myeloid and ot...

Chronic myeloid leukemia, conserved biosystemChronic myelogenous leukemia (CML) originates in a pluripotent hematopoetic stem cell of the bone marrow and is characterized by greatly increased numbers of granulocytes in the blood. Myeloid and ot...

Colorectal cancer, organism-specific biosystemColorectal cancer (CRC) is the second largest cause of cancer-related deaths in Western countries. CRC arises from the colorectal epithelium as a result of the accumulation of genetic alterations in ...

Colorectal cancer, conserved biosystemColorectal cancer (CRC) is the second largest cause of cancer-related deaths in Western countries. CRC arises from the colorectal epithelium as a result of the accumulation of genetic alterations in ...

DNA Damage/Telomere Stress Induced Senescence, organism-specific biosystemReactive oxygen species (ROS), whose concentration increases in senescent cells due to oncogenic RAS-induced mitochondrial dysfunction (Moiseeva et al. 2009) or due to environmental stress, cause DNA...

DNA Double Strand Break Response, organism-specific biosystemDNA double strand break (DSB) response involves sensing of DNA DSBs by the MRN complex which triggers ATM activation. ATM phosphorylates a number of proteins involved in DNA damage checkpoint signali...

DNA Double-Strand Break Repair, organism-specific biosystemNumerous types of DNA damage can occur within a cell due to the endogenous production of oxygen free radicals, normal alkylation reactions, or exposure to exogenous radiations and chemicals. Double-s...

DNA Repair, organism-specific biosystemDNA repair is a phenomenal multi-enzyme, multi-pathway system required to ensure the integrity of the cellular genome. Living organisms are constantly exposed to harmful metabolic by-products, enviro...

DNA damage response, organism-specific biosystemThis is the first pathway out of two pathways which deals with DNA damage response. It has two central gene products (ATM and ATR) which are connected to the sources of DNA damage (in blue). The two ...

DNA damage response (only ATM dependent), organism-specific biosystemThis is the second pathway out of two pathways which deals with DNA damage response. It has two central gene products (ATM and TP53) which are connected with the first DNA damage response pathway. In...

Delta-Notch Signaling Pathway, organism-specific biosystemThere are 4 Notch receptors in humans (Notch 1-4) that bind to a family of 5 ligands (Jagged 1 and 2 and Delta-like 1-3). The Notch receptors are expressed on the cell surface as heterodimeric protei...

Direct p53 effectors, organism-specific biosystem Direct p53 effectors

Endometrial cancer, organism-specific biosystemEndometrial cancer (EC) is the most common gynaecological malignancy and the fourth most common malignancy in women in the developed world after breast, colorectal and lung cancer. Two types of endom...

Endometrial cancer, conserved biosystemEndometrial cancer (EC) is the most common gynaecological malignancy and the fourth most common malignancy in women in the developed world after breast, colorectal and lung cancer. Two types of endom...

Epstein-Barr virus infection, organism-specific biosystemEpstein-Barr virus (EBV) is a ubiquitous human herpesvirus that is associated with oncogenesis. EBV infection to primary human B lymphocytes leads to induction of EBV-specific HLA-restricted cytotoxi...

Epstein-Barr virus infection, conserved biosystemEpstein-Barr virus (EBV) is a ubiquitous human herpesvirus that is associated with oncogenesis. EBV infection to primary human B lymphocytes leads to induction of EBV-specific HLA-restricted cytotoxi...

ErbB signaling pathway, organism-specific biosystemThe ErbB protein family or epidermal growth factor receptor (EGFR) family is a family of four structurally related receptor tyrosine kinases. Insufficient ErbB signaling in humans is associated with ...

Factors involved in megakaryocyte development and platelet production, organism-specific biosystemMegakaryocytes (MKs) give rise to circulating platelets (thrombocytes) through terminal differentiation of MKs which release cytoplasmic fragments as circulating platelets. As MKs mature they underg...

Fluoropyrimidine Activity, organism-specific biosystemThe main mechanism of 5-FU activation is conversion to fluorodeoxyuridine monophosphate (FdUMP) which inhibits the enzyme thymidylate synthase (TYMS), an important part of the folate-homocysteine cyc...

Formation of Senescence-Associated Heterochromatin Foci (SAHF), organism-specific biosystemThe process of DNA damage/telomere stress induced senescence culminates in the formation of senescence associated heterochromatin foci (SAHF). These foci represent facultative heterochromatin that is...

G1 to S cell cycle control, organism-specific biosystemIn the G1 phase there are two types of DNA damage responses, the p53-dependent and the p53-independent pathways. The p53-dependent responses inhibit CDKs through the up-regulation of genes encoding C...

G1/S DNA Damage Checkpoints, organism-specific biosystemIn the G1 phase there are two types of DNA damage responses, the p53-dependent and the p53-independent pathways. The p53-dependent responses inhibit CDKs through the up-regulation of genes encoding ...

G2/M Checkpoints, organism-specific biosystemG2/M checkpoints include the checks for damaged DNA, unreplicated DNA, and checks that ensure that the genome is replicated once and only once per cell cycle. If cells pass these checkpoints, they f...

G2/M DNA damage checkpoint, organism-specific biosystemThroughout the cell cycle, the genome is constantly monitored for damage, resulting either from errors of replication, by-products of metabolism or through extrinsic sources such as ultra-violet or i...

G2/M Transition, organism-specific biosystemCyclin A can also form complexes with Cdc2 (Cdk1). Together with three B-type cyclins, Cdc2 (Cdk1) regulates the transition from G2 into mitosis. These complexes are activated by dephosphorylation of...

Gastric cancer network 2, organism-specific biosystemNetwork generated by mapping candidate oncogenes and tumor suppressor genes identified by integrated analysis of expression array and aCGH data. Network generated by Ingenuity Pathway Analysis.

Gene Expression, organism-specific biosystemGene Expression covers the pathways by which genomic DNA is transcribed to yield RNA, the regulation of these transcription processes, and the pathways by which newly-made RNA Transcripts are process...

Generic Transcription Pathway, organism-specific biosystemOVERVIEW OF TRANSCRIPTION REGULATION: Detailed studies of gene transcription regulation in a wide variety of eukaryotic systems has revealed the general principles and mechanisms by which cell- or t...

Glioma, organism-specific biosystemGliomas are the most common of the primary brain tumors and account for more than 40% of all central nervous system neoplasms. Gliomas include tumours that are composed predominantly of astrocytes (a...

Glioma, conserved biosystemGliomas are the most common of the primary brain tumors and account for more than 40% of all central nervous system neoplasms. Gliomas include tumours that are composed predominantly of astrocytes (a...

Glucocorticoid receptor regulatory network, organism-specific biosystem Glucocorticoid receptor regulatory network

HTLV-I infection, organism-specific biosystemHuman T-lymphotropic virus type 1 (HTLV-1) is a pathogenic retrovirus that is associated with adult T-cell leukemia/lymphoma (ATL). It is also strongly implicated in non-neoplastic chronic inflammato...

HTLV-I infection, conserved biosystemHuman T-lymphotropic virus type 1 (HTLV-1) is a pathogenic retrovirus that is associated with adult T-cell leukemia/lymphoma (ATL). It is also strongly implicated in non-neoplastic chronic inflammato...

Hemostasis, organism-specific biosystemHemostasis is a physiological response that culminates in the arrest of bleeding from an injured vessel. Under normal conditions the vascular endothelium supports vasodilation, inhibits platelet adhe...

Hepatitis B, organism-specific biosystemHepatitis B virus (HBV) is an enveloped virus and contains a partially double-stranded relaxed circular DNA (RC-DNA) genome. After entry into hepatocytes, HBV RC-DNA is transported to the nucleus and...

Hepatitis C, organism-specific biosystemHepatitis C virus (HCV) is a major cause of chronic liver disease. The HCV employ several strategies to perturb host cell immunity. After invasion, HCV RNA genome functions directly as an mRNA in the...

Hepatitis C, conserved biosystemHepatitis C virus (HCV) is a major cause of chronic liver disease. The HCV employ several strategies to perturb host cell immunity. After invasion, HCV RNA genome functions directly as an mRNA in the...

Herpes simplex infection, organism-specific biosystemHerpes simplex virus (HSV) infections are very common worldwide, with the prevalence of HSV-1 reaching up to 80%-90%. Primary infection with HSV takes place in the mucosa, followed by the establishme...

Herpes simplex infection, conserved biosystemHerpes simplex virus (HSV) infections are very common worldwide, with the prevalence of HSV-1 reaching up to 80%-90%. Primary infection with HSV takes place in the mucosa, followed by the establishme...

Huntington's disease, organism-specific biosystemHuntington disease (HD) is an autosomal-dominant neurodegenerative disorder that primarily affects medium spiny striatal neurons (MSN). The symptoms are choreiform, involuntary movements, personality...

Huntington's disease, conserved biosystemHuntington disease (HD) is an autosomal-dominant neurodegenerative disorder that primarily affects medium spiny striatal neurons (MSN). The symptoms are choreiform, involuntary movements, personality...

Hypoxic and oxygen homeostasis regulation of HIF-1-alpha, organism-specific biosystem Hypoxic and oxygen homeostasis regulation of HIF-1-alpha

Integrated Breast Cancer Pathway, organism-specific biosystemThis pathway incorporates the most important proteins for Breast Cancer. The Rp score from the Connectivity-Maps (C-Maps) webserver was used to determine the rank of the most important proteins in Br...

Integrated Cancer pathway, organism-specific biosystem Integrated Cancer pathway

Integrated Pancreatic Cancer Pathway, organism-specific biosystemAn integrated pathway model which displays the protein-protein interactions (PPIs) among the relevant proteins for pancreatic cancer. This pathway is a collection of different mechanistic protein pat...

Intrinsic Pathway for Apoptosis, organism-specific biosystemThe intrinsic (Bcl-2 inhibitable or mitochondrial) pathway of apoptosis functions in response to various types of intracellular stress including growth factor withdrawal, DNA damage, unfolding stress...

LKB1 signaling events, organism-specific biosystem LKB1 signaling events

Longevity regulating pathway, organism-specific biosystemRegulation of longevity depends on genetic and environmental factors. Caloric restriction (CR), that is limiting food intake, is recognized in mammals as the best characterized and most reproducible ...

MAPK signaling pathway, organism-specific biosystemThe mitogen-activated protein kinase (MAPK) cascade is a highly conserved module that is involved in various cellular functions, including cell proliferation, differentiation and migration. Mammals e...

MAPK signaling pathway, organism-specific biosystemThe mitogen-activated protein kinase (MAPK) cascade is a highly conserved module that is involved in various cellular functions, including cell proliferation, differentiation and migration. Mammals e...

MAPK signaling pathway, conserved biosystemThe mitogen-activated protein kinase (MAPK) cascade is a highly conserved module that is involved in various cellular functions, including cell proliferation, differentiation and migration. Mammals e...

Measles, organism-specific biosystemMeasles virus (MV) is highly contagious virus that leads infant death worldwide. Humans are the unique natural reservoir for this virus. It causes severe immunosuppression favouring secondary bacteri...

Measles, conserved biosystemMeasles virus (MV) is highly contagious virus that leads infant death worldwide. Humans are the unique natural reservoir for this virus. It causes severe immunosuppression favouring secondary bacteri...

Melanoma, organism-specific biosystemMelanoma is a form of skin cancer that has a poor prognosis and which is on the rise in Western populations. Melanoma arises from the malignant transformation of pigment-producing cells, melanocytes...

Melanoma, conserved biosystemMelanoma is a form of skin cancer that has a poor prognosis and which is on the rise in Western populations. Melanoma arises from the malignant transformation of pigment-producing cells, melanocytes...

Metabolism of proteins, organism-specific biosystemProtein metabolism comprises the pathways of translation, post-translational modification and protein folding.

MicroRNAs in cancer, organism-specific biosystemMicroRNA (miRNA) is a cluster of small non-encoding RNA molecules of 21 - 23 nucleotides in length, which controls gene expression post-transcriptionally either via the degradation of target mRNAs or...

MicroRNAs in cancer, conserved biosystemMicroRNA (miRNA) is a cluster of small non-encoding RNA molecules of 21 - 23 nucleotides in length, which controls gene expression post-transcriptionally either via the degradation of target mRNAs or...

Mitotic G2-G2/M phases, organism-specific biosystem Mitotic G2-G2/M phases

Neurotrophin signaling pathway, organism-specific biosystemNeurotrophins are a family of trophic factors involved in differentiation and survival of neural cells. The neurotrophin family consists of nerve growth factor (NGF), brain derived neurotrophic facto...

Neurotrophin signaling pathway, conserved biosystemNeurotrophins are a family of trophic factors involved in differentiation and survival of neural cells. The neurotrophin family consists of nerve growth factor (NGF), brain derived neurotrophic facto...

Non-small cell lung cancer, organism-specific biosystemLung cancer is a leading cause of cancer death among men and women in industrialized countries. Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer and represents a heter...

Non-small cell lung cancer, conserved biosystemLung cancer is a leading cause of cancer death among men and women in industrialized countries. Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer and represents a heter...

Oncogene Induced Senescence, organism-specific biosystemOncogene-induced senescence is triggered by high level of RAS/RAF/MAPK signaling that can be caused, for example, by oncogenic mutations in RAS or RAF proteins, or by oncogenic mutations in growth fa...

Oncostatin M Signaling Pathway, organism-specific biosystemOncostatin M (OSM) is a member of the multifunctional cytokine interleukin 6 (IL6) - type cytokine family. It is mainly produced in cell types such as activated T lymphocytes, macrophages, monocytes,...

Oxidative Stress Induced Senescence, organism-specific biosystemOxidative stress, caused by increased concentration of reactive oxygen species (ROS) in the cell, can happen as a consequence of mitochondrial dysfunction induced by the oncogenic RAS (Moiseeva et al...

PI3K-Akt signaling pathway, organism-specific biosystemThe phosphatidylinositol 3' -kinase(PI3K)-Akt signaling pathway is activated by many types of cellular stimuli or toxic insults and regulates fundamental cellular functions such as transcription, tra...

PI3K-Akt signaling pathway, conserved biosystemThe phosphatidylinositol 3' -kinase(PI3K)-Akt signaling pathway is activated by many types of cellular stimuli or toxic insults and regulates fundamental cellular functions such as transcription, tra...

PLK3 signaling events, organism-specific biosystem PLK3 signaling events

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TP53 tumor protein p53 [ (human)] - Gene ID - 7157

AGE-RAGE signaling pathway in diabetic complications, organism-specific biosystemAdvanced glycation end products (AGEs) are a complex group of compounds produced through the non-enzymatic glycation and oxidation of proteins, lipids and nucleic acids, primarily due to aging and un...

AGE-RAGE signaling pathway in diabetic complications, conserved biosystemAdvanced glycation end products (AGEs) are a complex group of compounds produced through the non-enzymatic glycation and oxidation of proteins, lipids and nucleic acids, primarily due to aging and un...

Adipocytokine signaling pathway, organism-specific biosystemIncreased adipocyte volume and number are positively correlated with leptin production, and negatively correlated with production of adiponectin. Leptin is an important regulator of energy intake and...

Adipocytokine signaling pathway, conserved biosystemIncreased adipocyte volume and number are positively correlated with leptin production, and negatively correlated with production of adiponectin. Leptin is an important regulator of energy intake and...

Adipogenesis, organism-specific biosystemThe different classess of factors involved in adipogenesis are shown. Adipogenesis is the process by which fat cells differentiate from predadipocytes to adipocytes (fat cells). Adipose tissue, compo...

African trypanosomiasis, organism-specific biosystemTrypanosoma brucei, the parasite responsible for African trypanosomiasis (sleeping sickness), are spread by the tsetse fly in sub-Saharan Africa. The parasites are able to pass through the blood-brai...

African trypanosomiasis, conserved biosystemTrypanosoma brucei, the parasite responsible for African trypanosomiasis (sleeping sickness), are spread by the tsetse fly in sub-Saharan Africa. The parasites are able to pass through the blood-brai...

AhR pathway, organism-specific biosystem AhR pathway

Allograft Rejection, organism-specific biosystemThis pathway illustrates molecular interactions involved in the fundamental adaptive immune response for allograft destruction. This pathway was adapted in large part from the KEGG pathway http://www...

Allograft rejection, organism-specific biosystemAllograft rejection is the consequence of the recipient's alloimmune response to nonself antigens expressed by donor tissues. After transplantation of organ allografts, there are two pathways of anti...

Allograft rejection, conserved biosystemAllograft rejection is the consequence of the recipient's alloimmune response to nonself antigens expressed by donor tissues. After transplantation of organ allografts, there are two pathways of anti...

Alzheimer's disease, organism-specific biosystemAlzheimer's disease (AD) is a chronic disorder that slowly destroys neurons and causes serious cognitive disability. AD is associated with senile plaques and neurofibrillary tangles (NFTs). Amyloid-b...

Alzheimer's disease, conserved biosystemAlzheimer's disease (AD) is a chronic disorder that slowly destroys neurons and causes serious cognitive disability. AD is associated with senile plaques and neurofibrillary tangles (NFTs). Amyloid-b...

Alzheimers Disease, organism-specific biosystemThis pathway displays current genes, proteolytic events and other processes associated with the progression of Alzheimer's disease. This pathway was adapted from KEGG on 10/7/2011. Note: mitochondria...

Amoebiasis, organism-specific biosystemEntamoeba histolytica, an extracellular protozoan parasite is a human pathogen that invades the intestinal epithelium. Infection occurs on ingestion of contaminated water and food. The pathogenesis o...

Amoebiasis, conserved biosystemEntamoeba histolytica, an extracellular protozoan parasite is a human pathogen that invades the intestinal epithelium. Infection occurs on ingestion of contaminated water and food. The pathogenesis o...

Amyotrophic lateral sclerosis (ALS), organism-specific biosystemAmyotrophic lateral sclerosis (ALS) is a progressive, lethal, degenerative disorder of motor neurons. The hallmark of this disease is the selective death of motor neurons in the brain and spinal cord...

Amyotrophic lateral sclerosis (ALS), organism-specific biosystemAmyotrophic lateral sclerosis (ALS) is a progressive, lethal, degenerative disorder of motor neurons. The hallmark of this disease is the selective death of motor neurons in the brain and spinal cord...

Amyotrophic lateral sclerosis (ALS), conserved biosystemAmyotrophic lateral sclerosis (ALS) is a progressive, lethal, degenerative disorder of motor neurons. The hallmark of this disease is the selective death of motor neurons in the brain and spinal cord...

Angiopoietin receptor Tie2-mediated signaling, organism-specific biosystem Angiopoietin receptor Tie2-mediated signaling

Antigen processing and presentation, organism-specific biosystem Antigen processing and presentation

Antigen processing and presentation, conserved biosystem Antigen processing and presentation

Apoptosis, organism-specific biosystemApoptosis is a distinct form of cell death that is functionally and morphologically different from necrosis. Nuclear chromatin condensation, cytoplasmic shrinking, dilated endoplasmic reticulum, and ...

Apoptosis, organism-specific biosystemApoptosis is a genetically programmed process for the elimination of damaged or redundant cells by activation of caspases (aspartate-specific cysteine proteases). The onset of apoptosis is controlled...

Apoptosis, conserved biosystemApoptosis is a genetically programmed process for the elimination of damaged or redundant cells by activation of caspases (aspartate-specific cysteine proteases). The onset of apoptosis is controlled...

Asthma, organism-specific biosystemAsthma is a complex syndrome with many clinical phenotypes in both adults and children. Its major characteristics include a variable degree of airflow obstruction, bronchial hyperresponsiveness, and ...

Asthma, conserved biosystemAsthma is a complex syndrome with many clinical phenotypes in both adults and children. Its major characteristics include a variable degree of airflow obstruction, bronchial hyperresponsiveness, and ...

Calcineurin-regulated NFAT-dependent transcription in lymphocytes, organism-specific biosystem Calcineurin-regulated NFAT-dependent transcription in lymphocytes

Canonical NF-kappaB pathway, organism-specific biosystem Canonical NF-kappaB pathway

Caspase cascade in apoptosis, organism-specific biosystem Caspase cascade in apoptosis

Cellular roles of Anthrax toxin, organism-specific biosystem Cellular roles of Anthrax toxin

Ceramide signaling pathway, organism-specific biosystem Ceramide signaling pathway

Chagas disease (American trypanosomiasis), organism-specific biosystemTrypanosoma cruzi is an intracellular protozoan parasite that causes Chagas disease. The parasite life cycle involves hematophagous reduviid bugs as vectors. Once parasites enter the host body, they ...

Chagas disease (American trypanosomiasis), conserved biosystemTrypanosoma cruzi is an intracellular protozoan parasite that causes Chagas disease. The parasite life cycle involves hematophagous reduviid bugs as vectors. Once parasites enter the host body, they ...

Cytokine Signaling in Immune system, organism-specific biosystemCytokines are small proteins that regulate and mediate immunity, inflammation, and hematopoiesis. They are secreted in response to immune stimuli, and usually act briefly, locally, at very low concen...

Cytokine-cytokine receptor interaction, organism-specific biosystemCytokines are soluble extracellular proteins or glycoproteins that are crucial intercellular regulators and mobilizers of cells engaged in innate as well as adaptive inflammatory host defenses, cell ...

Cytokine-cytokine receptor interaction, conserved biosystemCytokines are soluble extracellular proteins or glycoproteins that are crucial intercellular regulators and mobilizers of cells engaged in innate as well as adaptive inflammatory host defenses, cell ...

Cytokines and Inflammatory Response, organism-specific biosystemInflammation is a protective response to infection by the immune system that requires communication between different classes of immune cells to coordinate their actions. Acute inflammation is an imp...

Death Receptor Signalling, organism-specific biosystemThe death receptors, all cell-surface receptors, begin the process of caspase activation. The common feature of these type 1 transmembrane proteins is the "death-domain" a conserved cytoplasmic motif...

Developmental Biology, organism-specific biosystemAs a first step towards capturing the array of processes by which a fertilized egg gives rise to the diverse tissues of the body, examples of three kinds of processes have been annotated. These are a...

Dilated cardiomyopathy, organism-specific biosystemDilated cardiomyopathy (DCM) is a heart muscle disease characterised by dilation and impaired contraction of the left or both ventricles that results in progressive heart failure and sudden cardiac d...

Dilated cardiomyopathy, conserved biosystemDilated cardiomyopathy (DCM) is a heart muscle disease characterised by dilation and impaired contraction of the left or both ventricles that results in progressive heart failure and sudden cardiac d...

Downstream signaling in naive CD8+ T cells, organism-specific biosystem Downstream signaling in naive CD8+ T cells

EBV LMP1 signaling, organism-specific biosystembased on science-slides...

FAS pathway and Stress induction of HSP regulation, organism-specific biosystemThis pathway describes the Fas induced apoptosis and interplay with Hsp27 in response to stress. More info: [http://www.biocarta.com/pathfiles/h_hsp27Pathway.asp BioCarta].

Fc epsilon RI signaling pathway, organism-specific biosystemFc epsilon RI-mediated signaling pathways in mast cells are initiated by the interaction of antigen (Ag) with IgE bound to the extracellular domain of the alpha chain of Fc epsilon RI. The activation...

Fc epsilon RI signaling pathway, conserved biosystemFc epsilon RI-mediated signaling pathways in mast cells are initiated by the interaction of antigen (Ag) with IgE bound to the extracellular domain of the alpha chain of Fc epsilon RI. The activation...

Graft-versus-host disease, organism-specific biosystemGraft-versus-host disease (GVHD) is a lethal complication of allogeneic hematopoietic stem cell transplantation (HSCT) where immunocompetent donor T cells attack the genetically disparate host cells....

Graft-versus-host disease, conserved biosystemGraft-versus-host disease (GVHD) is a lethal complication of allogeneic hematopoietic stem cell transplantation (HSCT) where immunocompetent donor T cells attack the genetically disparate host cells....

HIV-1 Nef: Negative effector of Fas and TNF-alpha, organism-specific biosystem HIV-1 Nef: Negative effector of Fas and TNF-alpha

HTLV-I infection, organism-specific biosystemHuman T-lymphotropic virus type 1 (HTLV-1) is a pathogenic retrovirus that is associated with adult T-cell leukemia/lymphoma (ATL). It is also strongly implicated in non-neoplastic chronic inflammato...

HTLV-I infection, conserved biosystemHuman T-lymphotropic virus type 1 (HTLV-1) is a pathogenic retrovirus that is associated with adult T-cell leukemia/lymphoma (ATL). It is also strongly implicated in non-neoplastic chronic inflammato...

Hematopoietic cell lineage, organism-specific biosystemBlood-cell development progresses from a hematopoietic stem cell (HSC), which can undergo either self-renewal or differentiation into a multilineage committed progenitor cell: a common lymphoid proge...

Hematopoietic cell lineage, conserved biosystemBlood-cell development progresses from a hematopoietic stem cell (HSC), which can undergo either self-renewal or differentiation into a multilineage committed progenitor cell: a common lymphoid proge...

Hepatitis B, organism-specific biosystemHepatitis B virus (HBV) is an enveloped virus and contains a partially double-stranded relaxed circular DNA (RC-DNA) genome. After entry into hepatocytes, HBV RC-DNA is transported to the nucleus and...

Hepatitis C, organism-specific biosystemHepatitis C virus (HCV) is a major cause of chronic liver disease. The HCV employ several strategies to perturb host cell immunity. After invasion, HCV RNA genome functions directly as an mRNA in the...

Hepatitis C, conserved biosystemHepatitis C virus (HCV) is a major cause of chronic liver disease. The HCV employ several strategies to perturb host cell immunity. After invasion, HCV RNA genome functions directly as an mRNA in the...

Herpes simplex infection, organism-specific biosystemHerpes simplex virus (HSV) infections are very common worldwide, with the prevalence of HSV-1 reaching up to 80%-90%. Primary infection with HSV takes place in the mucosa, followed by the establishme...

Herpes simplex infection, conserved biosystemHerpes simplex virus (HSV) infections are very common worldwide, with the prevalence of HSV-1 reaching up to 80%-90%. Primary infection with HSV takes place in the mucosa, followed by the establishme...

Hypertrophic cardiomyopathy (HCM), organism-specific biosystemHypertrophic cardiomyopathy (HCM) is a primary myocardial disorder with an autosomal dominant pattern of inheritance that is characterized by hypertrophy of the left ventricles with histological feat...

Hypertrophic cardiomyopathy (HCM), conserved biosystemHypertrophic cardiomyopathy (HCM) is a primary myocardial disorder with an autosomal dominant pattern of inheritance that is characterized by hypertrophy of the left ventricles with histological feat...

IL23-mediated signaling events, organism-specific biosystem IL23-mediated signaling events

IL27-mediated signaling events, organism-specific biosystem IL27-mediated signaling events

Immune System, organism-specific biosystemHumans are exposed to millions of potential pathogens daily, through contact, ingestion, and inhalation. Our ability to avoid infection depends on the adaptive immune system and during the first crit...

Inflammatory bowel disease (IBD), organism-specific biosystemInflammatory bowel disease (IBD), which includes Crohn disease (CD) and ulcerative colitis (UC), is characterized by chronic inflammation of the gastrointestinal tract due to environmental and geneti...

Inflammatory bowel disease (IBD), conserved biosystemInflammatory bowel disease (IBD), which includes Crohn disease (CD) and ulcerative colitis (UC), is characterized by chronic inflammation of the gastrointestinal tract due to environmental and geneti...

Influenza A, organism-specific biosystemInfluenza is a contagious respiratory disease caused by influenza virus infection. Influenza A virus is responsible for both annual seasonal epidemics and periodic worldwide pandemics. Novel strains ...

Influenza A, conserved biosystemInfluenza is a contagious respiratory disease caused by influenza virus infection. Influenza A virus is responsible for both annual seasonal epidemics and periodic worldwide pandemics. Novel strains ...

Insulin resistance, organism-specific biosystemInsulin resistance is a condition where cells become resistant to the effects of insulin. It is often found in people with health disorders, including obesity, type 2 diabetes mellitus, non-alcoholic...

Integrated Pancreatic Cancer Pathway, organism-specific biosystemAn integrated pathway model which displays the protein-protein interactions (PPIs) among the relevant proteins for pancreatic cancer. This pathway is a collection of different mechanistic protein pat...

Legionellosis, organism-specific biosystemLegionellosis is a potentially fatal infectious disease caused by the bacterium Legionella pneumophila and other legionella species. Two distinct clinical and epidemiological syndromes are associated...

Legionellosis, conserved biosystemLegionellosis is a potentially fatal infectious disease caused by the bacterium Legionella pneumophila and other legionella species. Two distinct clinical and epidemiological syndromes are associated...

Leishmaniasis, organism-specific biosystemLeishmania is an intracellular protozoan parasite of macrophages that causes visceral, mucosal, and cutaneous diseases. The parasite is transmitted to humans by sandflies, where they survive and prol...

Leishmaniasis, conserved biosystemLeishmania is an intracellular protozoan parasite of macrophages that causes visceral, mucosal, and cutaneous diseases. The parasite is transmitted to humans by sandflies, where they survive and prol...

MAPK signaling pathway, organism-specific biosystemThe mitogen-activated protein kinase (MAPK) cascade is a highly conserved module that is involved in various cellular functions, including cell proliferation, differentiation and migration. Mammals e...

MAPK signaling pathway, organism-specific biosystemThe mitogen-activated protein kinase (MAPK) cascade is a highly conserved module that is involved in various cellular functions, including cell proliferation, differentiation and migration. Mammals e...

MAPK signaling pathway, conserved biosystemThe mitogen-activated protein kinase (MAPK) cascade is a highly conserved module that is involved in various cellular functions, including cell proliferation, differentiation and migration. Mammals e...

Malaria, organism-specific biosystemPlasmodium protozoa are parasites that account for malaria infection. Sporozoite forms of the parasite are injected by mosquito bites under the skin and are carried to the liver where they develop in...

Malaria, conserved biosystemPlasmodium protozoa are parasites that account for malaria infection. Sporozoite forms of the parasite are injected by mosquito bites under the skin and are carried to the liver where they develop in...

Matrix Metalloproteinases, organism-specific biosystemMatrix metalloproteinases (MMPs) are zinc-dependent endopeptidases; other family members are adamalysins, serralysins, and astacins. The MMPs belong to a larger family of proteases known as the metzi...

MicroRNAs in cardiomyocyte hypertrophy, organism-specific biosystemThis pathway shows the role of microRNAs in the process of cardiac hypertrophy. MicroRNA targets were predicted by the TargetScan algorithm, and the predicted interactions are shown in red dashed lin...

Monoamine Transport, organism-specific biosystem Monoamine Transport

NF-kappa B signaling pathway, organism-specific biosystemNuclear factor-kappa B (NF-kappa B) is the generic name of a family of transcription factors that function as dimers and regulate genes involved in immunity, inflammation and cell survival. There are...

NF-kappa B signaling pathway, conserved biosystemNuclear factor-kappa B (NF-kappa B) is the generic name of a family of transcription factors that function as dimers and regulate genes involved in immunity, inflammation and cell survival. There are...

NOD-like receptor signaling pathway, organism-specific biosystemSpecific families of pattern recognition receptors are responsible for detecting various pathogens and generating innate immune responses. The intracellular NOD-like receptor (NLR) family contains mo...

NOD-like receptor signaling pathway, conserved biosystemSpecific families of pattern recognition receptors are responsible for detecting various pathogens and generating innate immune responses. The intracellular NOD-like receptor (NLR) family contains mo...

Natural killer cell mediated cytotoxicity, organism-specific biosystemNatural killer (NK) cells are lymphocytes of the innate immune system that are involved in early defenses against both allogeneic (nonself) cells and autologous cells undergoing various forms of stre...

Natural killer cell mediated cytotoxicity, conserved biosystemNatural killer (NK) cells are lymphocytes of the innate immune system that are involved in early defenses against both allogeneic (nonself) cells and autologous cells undergoing various forms of stre...

Non-alcoholic fatty liver disease (NAFLD), organism-specific biosystemNon-alcoholic fatty liver disease (NAFLD) represents a spectrum ranging from simple steatosis to more severe steatohepatitis with hepatic inflammation and fibrosis, known as nonalcoholic steatohepati...

Non-alcoholic fatty liver disease (NAFLD), conserved biosystemNon-alcoholic fatty liver disease (NAFLD) represents a spectrum ranging from simple steatosis to more severe steatohepatitis with hepatic inflammation and fibrosis, known as nonalcoholic steatohepati...

Notch Signaling Pathway, organism-specific biosystemThe Notch signaling pathway is an evolutionarily conserved, intercellular signaling mechanism essential for proper embryonic development in all metazoan organisms in the Animal kingdom. The Notch pro...

Osteoclast differentiation, organism-specific biosystemThe osteoclasts, multinucleared cells originating from the hematopoietic monocyte-macrophage lineage, are responsible for bone resorption. Osteoclastogenesis is mainly regulated by signaling pathways...

Osteoclast differentiation, conserved biosystemThe osteoclasts, multinucleared cells originating from the hematopoietic monocyte-macrophage lineage, are responsible for bone resorption. Osteoclastogenesis is mainly regulated by signaling pathways...

Pertussis, organism-specific biosystemPertussis, also known as whooping cough, is an acute respiratory infectious disease caused by a bacteria called Bordetella Pertussis. The characteristic symptoms are paroxysmal cough, inspiratory whe...

Pertussis, conserved biosystemPertussis, also known as whooping cough, is an acute respiratory infectious disease caused by a bacteria called Bordetella Pertussis. The characteristic symptoms are paroxysmal cough, inspiratory whe...

Proteoglycans in cancer, organism-specific biosystemMany proteoglycans (PGs) in the tumor microenvironment have been shown to be key macromolecules that contribute to biology of various types of cancer including proliferation, adhesion, angiogenesis a...

Proteoglycans in cancer, conserved biosystemMany proteoglycans (PGs) in the tumor microenvironment have been shown to be key macromolecules that contribute to biology of various types of cancer including proliferation, adhesion, angiogenesis a...

RIG-I-like receptor signaling pathway, organism-specific biosystemSpecific families of pattern recognition receptors are responsible for detecting viral pathogens and generating innate immune responses. Non-self RNA appearing in a cell as a result of intracellular ...

RIG-I-like receptor signaling pathway, conserved biosystemSpecific families of pattern recognition receptors are responsible for detecting viral pathogens and generating innate immune responses. Non-self RNA appearing in a cell as a result of intracellular ...

RXR and RAR heterodimerization with other nuclear receptor, organism-specific biosystem RXR and RAR heterodimerization with other nuclear receptor

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TNF tumor necrosis factor [ (human)]

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Cystic fibrosis (CF) is a genetic disorder that affects mostly the lungs but also the pancreas, liver, kidneys, and intestine.[1][2] Long-term issues include difficulty breathing and coughing up mucus as a result of frequent lung infections. Other signs and symptoms include sinus infections, poor growth, fatty stool, clubbing of the fingers and toes, and infertility in males, among others. Different people may have different degrees of symptoms.[1]

CF is inherited in an autosomal recessive manner. It is caused by the presence of mutations in both copies of the gene for the cystic fibrosis transmembrane conductance regulator (CFTR) protein.[1] Those with a single working copy are carriers and otherwise mostly normal.[3] CFTR is involved in production of sweat, digestive fluids, and mucus.[4] When CFTR is not functional, secretions which are usually thin instead become thick.[5] The condition is diagnosed by a sweat test and genetic testing.[1] Screening of infants at birth takes place in some areas of the world.[1]

There is no cure for cystic fibrosis.[3] Lung infections are treated with antibiotics which may be given intravenously, inhaled, or by mouth. Sometimes the antibiotic azithromycin is used long term. Inhaled hypertonic saline and salbutamol may also be useful. Lung transplantation may be an option if lung function continues to worsen. Pancreatic enzyme replacement and fat-soluble vitamin supplementation are important, especially in the young.[1]Airway clearance techniques such as chest physiotherapy have some short term benefit but long term effects are unclear.[6] The average life expectancy is between 42 and 50 years in the developed world.[7][8] Lung problems are responsible for death in 80% of people with cystic fibrosis.[1]

CF is most common among people of Northern European ancestry and affects about one out of every 3,000 newborns.[1] About one in 25 people are carriers.[3] It is least common in Africans and Asians.[1] It was first recognized as a specific disease by Dorothy Andersen in 1938, with descriptions that fit the condition occurring at least as far back as 1595.[2] The name cystic fibrosis refers to the characteristic fibrosis and cysts that form within the pancreas.[2][9]

The main signs and symptoms of cystic fibrosis are salty-tasting skin,[10] poor growth, and poor weight gain despite normal food intake,[11] accumulation of thick, sticky mucus,[12] frequent chest infections, and coughing or shortness of breath.[13] Males can be infertile due to congenital absence of the vas deferens.[14] Symptoms often appear in infancy and childhood, such as bowel obstruction due to meconium ileus in newborn babies.[15] As the children grow, they exercise to release mucus in the alveoli.[16]Ciliated epithelial cells in the person have a mutated protein that leads to abnormally viscous mucus production.[12] The poor growth in children typically presents as an inability to gain weight or height at the same rate as their peers and is occasionally not diagnosed until investigation is initiated for poor growth. The causes of growth failure are multifactorial and include chronic lung infection, poor absorption of nutrients through the gastrointestinal tract, and increased metabolic demand due to chronic illness.[11]

In rare cases, cystic fibrosis can manifest itself as a coagulation disorder. Vitamin K is normally absorbed from breast milk, formula, and later, solid foods. This absorption is impaired in some cystic fibrosis patients. Young children are especially sensitive to vitamin K malabsorptive disorders because only a very small amount of vitamin K crosses the placenta, leaving the child with very low reserves and limited ability to absorb vitamin K from dietary sources after birth. Because factors II, VII, IX, and X (clotting factors) are vitamin Kdependent, low levels of vitamin K can result in coagulation problems. Consequently, when a child presents with unexplained bruising, a coagulation evaluation may be warranted to determine whether there is an underlying disease.[17]

Lung disease results from clogging of the airways due to mucus build-up, decreased mucociliary clearance, and resulting inflammation.[18][19] Inflammation and infection cause injury and structural changes to the lungs, leading to a variety of symptoms. In the early stages, incessant coughing, copious phlegm production, and decreased ability to exercise are common. Many of these symptoms occur when bacteria that normally inhabit the thick mucus grow out of control and cause pneumonia. In later stages, changes in the architecture of the lung, such as pathology in the major airways (bronchiectasis), further exacerbate difficulties in breathing. Other signs include coughing up blood (hemoptysis), high blood pressure in the lung (pulmonary hypertension), heart failure, difficulties getting enough oxygen to the body (hypoxia), and respiratory failure requiring support with breathing masks, such as bilevel positive airway pressure machines or ventilators.[20]Staphylococcus aureus, Haemophilus influenzae, and Pseudomonas aeruginosa are the three most common organisms causing lung infections in CF patients.[19] In addition to typical bacterial infections, people with CF more commonly develop other types of lung disease. Among these is allergic bronchopulmonary aspergillosis, in which the body's response to the common fungus Aspergillus fumigatus causes worsening of breathing problems. Another is infection with Mycobacterium avium complex (MAC), a group of bacteria related to tuberculosis, which can cause a lot of lung damage and does not respond to common antibiotics.[21]

Mucus in the paranasal sinuses is equally thick and may also cause blockage of the sinus passages, leading to infection. This may cause facial pain, fever, nasal drainage, and headaches. Individuals with CF may develop overgrowth of the nasal tissue (nasal polyps) due to inflammation from chronic sinus infections.[22] Recurrent sinonasal polyps can occur in as many as 10% to 25% of CF patients.[19] These polyps can block the nasal passages and increase breathing difficulties.[23][24]

Cardiorespiratory complications are the most common cause of death (~80%) in patients at most CF centers in the United States.[19]

Prior to prenatal and newborn screening, cystic fibrosis was often diagnosed when a newborn infant failed to pass feces (meconium). Meconium may completely block the intestines and cause serious illness. This condition, called meconium ileus, occurs in 510%[19][25] of newborns with CF. In addition, protrusion of internal rectal membranes (rectal prolapse) is more common, occurring in as many as 10% of children with CF,[19] and it is caused by increased fecal volume, malnutrition, and increased intraabdominal pressure due to coughing.[26]

The thick mucus seen in the lungs has a counterpart in thickened secretions from the pancreas, an organ responsible for providing digestive juices that help break down food. These secretions block the exocrine movement of the digestive enzymes into the duodenum and result in irreversible damage to the pancreas, often with painful inflammation (pancreatitis).[27] The pancreatic ducts are totally plugged in more advanced cases, usually seen in older children or adolescents.[19] This causes atrophy of the exocrine glands and progressive fibrosis.[19]

The lack of digestive enzymes leads to difficulty absorbing nutrients with their subsequent excretion in the feces, a disorder known as malabsorption. Malabsorption leads to malnutrition and poor growth and development because of calorie loss. Resultant hypoproteinemia may be severe enough to cause generalized edema.[19] Individuals with CF also have difficulties absorbing the fat-soluble vitamins A, D, E, and K.

In addition to the pancreas problems, people with cystic fibrosis experience more heartburn, intestinal blockage by intussusception, and constipation.[28] Older individuals with CF may develop distal intestinal obstruction syndrome when thickened feces cause intestinal blockage.[29]

Exocrine pancreatic insufficiency occurs in the majority (85% to 90%) of patients with CF.[19] It is mainly associated with "severe" CFTR mutations, where both alleles are completely nonfunctional (e.g. F508/F508).[19] It occurs in 10% to 15% of patients with one "severe" and one "mild" CFTR mutation where there still is a little CFTR activity, or where there are two "mild" CFTR mutations.[19] In these milder cases, there is still sufficient pancreatic exocrine function so that enzyme supplementation is not required.[19] There are usually no other GI complications in pancreas-sufficient phenotypes, and in general, such individuals usually have excellent growth and development.[19] Despite this, idiopathic chronic pancreatitis can occur in a subset of pancreas-sufficient individuals with CF, and is associated with recurrent abdominal pain and life-threatening complications.[19]

Thickened secretions also may cause liver problems in patients with CF. Bile secreted by the liver to aid in digestion may block the bile ducts, leading to liver damage. Over time, this can lead to scarring and nodularity (cirrhosis). The liver fails to rid the blood of toxins and does not make important proteins, such as those responsible for blood clotting.[30][31] Liver disease is the third most common cause of death associated with CF.[19]

The pancreas contains the islets of Langerhans, which are responsible for making insulin, a hormone that helps regulate blood glucose. Damage of the pancreas can lead to loss of the islet cells, leading to a type of diabetes that is unique to those with the disease.[32] This cystic fibrosis-related diabetes (CFRD) shares characteristics that can be found in type 1 and type 2 diabetics, and is one of the principal nonpulmonary complications of CF.[33]Vitamin D is involved in calcium and phosphate regulation. Poor uptake of vitamin D from the diet because of malabsorption can lead to the bone disease osteoporosis in which weakened bones are more susceptible to fractures.[34] In addition, people with CF often develop clubbing of their fingers and toes due to the effects of chronic illness and low oxygen in their tissues.[35][36]

Infertility affects both men and women. At least 97% of men with cystic fibrosis are infertile, but not sterile and can have children with assisted reproductive techniques.[37] The main cause of infertility in men with cystic fibrosis is congenital absence of the vas deferens (which normally connects the testes to the ejaculatory ducts of the penis), but potentially also by other mechanisms such as causing no sperm, teratospermia, and few sperm with poor motility.[38] Many men found to have congenital absence of the vas deferens during evaluation for infertility have a mild, previously undiagnosed form of CF.[39] Approximately 20% of women with CF have fertility difficulties due to thickened cervical mucus or malnutrition. In severe cases, malnutrition disrupts ovulation and causes a lack of menstruation.[40]

CF is caused by a mutation in the gene cystic fibrosis transmembrane conductance regulator (CFTR). The most common mutation, F508, is a deletion ( signifying deletion) of three nucleotides[41] that results in a loss of the amino acid phenylalanine (F) at the 508th position on the protein. This mutation accounts for two-thirds (6670%[19]) of CF cases worldwide and 90% of cases in the United States; however, there are over 1500 other mutations that can produce CF.[42] Although most people have two working copies (alleles) of the CFTR gene, only one is needed to prevent cystic fibrosis. CF develops when neither allele can produce a functional CFTR protein. Thus, CF is considered an autosomal recessive disease.

The CFTR gene, found at the q31.2 locus of chromosome 7, is 230,000 base pairs long, and creates a protein that is 1,480 amino acids long. More specifically the location is between base pair 117,120,016 to 117,308,718 on the long arm of chromosome 7, region 3, band 1, sub-band 2, represented as 7q31.2. Structurally, CFTR is a type of gene known as an ABC gene. The product of this gene (the CFTR) is a chloride ion channel important in creating sweat, digestive juices and mucus. This protein possesses two ATP-hydrolyzing domains, which allows the protein to use energy in the form of ATP. It also contains two domains comprising 6 alpha helices apiece, which allow the protein to cross the cell membrane. A regulatory binding site on the protein allows activation by phosphorylation, mainly by cAMP-dependent protein kinase.[20] The carboxyl terminal of the protein is anchored to the cytoskeleton by a PDZ domain interaction.[43]

In addition, there is increasing evidence that genetic modifiers besides CFTR modulate the frequency and severity of the disease. One example is mannan-binding lectin, which is involved in innate immunity by facilitating phagocytosis of microorganisms. Polymorphisms in one or both mannan-binding lectin alleles that result in lower circulating levels of the protein are associated with a threefold higher risk of end-stage lung disease, as well as an increased burden of chronic bacterial infections.[19]

There are several mutations in the CFTR gene, and different mutations cause different defects in the CFTR protein, sometimes causing a milder or more severe disease. These protein defects are also targets for drugs which can sometimes restore their function. F508-CFTR, which occurs in >90% of patients in the U.S., creates a protein that does not fold normally and is not appropriately transported to the cell membrane, resulting in its degradation. Other mutations result in proteins that are too short (truncated) because production is ended prematurely. Other mutations produce proteins that: do not use energy normally, do not allow chloride, iodide, and thiocyanate to cross the membrane appropriately,[44] degrade at a faster rate than normal. Mutations may also lead to fewer copies of the CFTR protein being produced.[20]

The protein created by this gene is anchored to the outer membrane of cells in the sweat glands, lungs, pancreas, and all other remaining exocrine glands in the body. The protein spans this membrane and acts as a channel connecting the inner part of the cell (cytoplasm) to the surrounding fluid. This channel is primarily responsible for controlling the movement of halogens from inside to outside of the cell; however, in the sweat ducts, it facilitates the movement of chloride from the sweat duct into the cytoplasm. When the CFTR protein does not resorb ions in sweat ducts, chloride and thiocyanate[45] released from sweat glands are trapped inside the ducts and pumped to the skin. Additionally hypothiocyanite, OSCN, cannot be produced by the immune defense system.[46][47] Because chloride is negatively charged, this modifies the electrical potential inside and outside the cell that normally causes cations to cross into the cell. Sodium is the most common cation in the extracellular space. The excess chloride within sweat ducts prevents sodium resorption by epithelial sodium channels and the combination of sodium and chloride creates the salt, which is lost in high amounts in the sweat of individuals with CF. This lost salt forms the basis for the sweat test.[20]

Most of the damage in CF is due to blockage of the narrow passages of affected organs with thickened secretions. These blockages lead to remodeling and infection in the lung, damage by accumulated digestive enzymes in the pancreas, blockage of the intestines by thick faeces, etc. There are several theories on how the defects in the protein and cellular function cause the clinical effects. The most current theory suggests that defective ion transport leads to dehydration in the airway epithelia, thickening mucus. In airway epithelial cells, the cilia exist in between the cell's apical surface and mucus in a layer known as Airway Surface Liquid (ASL). The flow of ions from the cell and into this layer is determined by ion channels like CFTR. CFTR not only allows Chloride ions to be drawn from the cell and into the ASL, but it also regulates another channel called ENac. ENac allows sodium ions to leave the ASL and enter the respiratory epithelium. CFTR normally inhibits this channel, but if the CFTR is defective, then sodium will flow freely from the ASL and into the cell. As water follows sodium, the depth of ASL will be depleted and the cilia will be left in the mucous layer.[48] As cilia cannot effectively move in a thick viscous environment, there is deficient mucociliary clearance and a buildup of mucus, clogging small airways.[49] The accumulation of more viscous, nutrient-rich mucus in the lungs allows bacteria to hide from the body's immune system, causing repeated respiratory infections. The presence of the same CFTR proteins in pancreatic duct and skin cells are what cause symptoms in these systems.

The lungs of individuals with cystic fibrosis are colonized and infected by bacteria from an early age. These bacteria, which often spread among individuals with CF, thrive in the altered mucus, which collects in the small airways of the lungs. This mucus leads to the formation of bacterial microenvironments known as biofilms that are difficult for immune cells and antibiotics to penetrate. Viscous secretions and persistent respiratory infections repeatedly damage the lung by gradually remodeling the airways, which makes infection even more difficult to eradicate.[50]

Over time, both the types of bacteria and their individual characteristics change in individuals with CF. In the initial stage, common bacteria such as Staphylococcus aureus and Haemophilus influenzae colonize and infect the lungs.[19] Eventually, Pseudomonas aeruginosa (and sometimes Burkholderia cepacia) dominates. By 18 years of age, 80% of patients with classic CF harbor P. aeruginosa, and 3.5% harbor B. cepacia.[19] Once within the lungs, these bacteria adapt to the environment and develop resistance to commonly used antibiotics. Pseudomonas can develop special characteristics that allow the formation of large colonies, known as "mucoid" Pseudomonas, which are rarely seen in people that do not have CF.[50] Scientific evidences suggest that Interleukin 17 pathway plays a key role in resistance and modulation of the inflammatory response during P. aeruginosa infection in CF.[51] In particular, Interleukin 17 -mediated immunity plays a double-edged activity during chronic airways infection: on one side, it contributes to the control of P. aeruginosa burden while, on the other, it propagates exacerbated pulmonary neutrophilia and tissue remodeling.[51]

One way infection spreads is by passing between different individuals with CF.[52] In the past, people with CF often participated in summer "CF Camps" and other recreational gatherings.[53][54] Hospitals grouped patients with CF into common areas and routine equipment (such as nebulizers)[55] was not sterilized between individual patients.[56] This led to transmission of more dangerous strains of bacteria among groups of patients. As a result, individuals with CF are now routinely isolated from one another in the healthcare setting, and healthcare providers are encouraged to wear gowns and gloves when examining patients with CF to limit the spread of virulent bacterial strains.[57]

CF patients may also have their airways chronically colonized by filamentous fungi (such as Aspergillus fumigatus, Scedosporium apiospermum, Aspergillus terreus) and/or yeasts (such as Candida albicans); other filamentous fungi less commonly isolated include Aspergillus flavus and Aspergillus nidulans (occur transiently in CF respiratory secretions) and Exophiala dermatitidis and Scedosporium prolificans (chronic airway-colonizers); some filamentous fungi like Penicillium emersonii and Acrophialophora fusispora are encountered in patients almost exclusively in the context of CF.[58] Defective mucociliary clearance characterizing CF is associated with local immunological disorders. In addition, the prolonged therapy with antibiotics and the use of corticosteroid treatments may also facilitate fungal growth. Although the clinical relevance of the fungal airway colonization is still a matter of debate, filamentous fungi may contribute to the local inflammatory response and therefore to the progressive deterioration of the lung function, as often happens with allergic broncho-pulmonary aspergillosis (ABPA) the most common fungal disease in the context of CF, involving a Th2-driven immune response to Aspergillus.[58][59]

Cystic fibrosis may be diagnosed by many different methods including newborn screening, sweat testing, and genetic testing.[60] As of 2006 in the United States, 10 percent of cases are diagnosed shortly after birth as part of newborn screening programs. The newborn screen initially measures for raised blood concentration of immunoreactive trypsinogen.[61] Infants with an abnormal newborn screen need a sweat test to confirm the CF diagnosis. In many cases, a parent makes the diagnosis because the infant tastes salty.[19]Trypsinogen levels can be increased in individuals who have a single mutated copy of the CFTR gene (carriers) or, in rare instances, in individuals with two normal copies of the CFTR gene. Due to these false positives, CF screening in newborns can be controversial.[62][63] Most states and countries do not screen for CF routinely at birth. Therefore, most individuals are diagnosed after symptoms (e.g. sinopulmonary disease and GI manifestations[19]) prompt an evaluation for cystic fibrosis. The most commonly used form of testing is the sweat test. Sweat-testing involves application of a medication that stimulates sweating (pilocarpine). To deliver the medication through the skin, iontophoresis is used to, whereby one electrode is placed onto the applied medication and an electric current is passed to a separate electrode on the skin. The resultant sweat is then collected on filter paper or in a capillary tube and analyzed for abnormal amounts of sodium and chloride. People with CF have increased amounts of sodium and chloride in their sweat. In contrast, people with CF have less thiocyanate and hypothiocyanite in their saliva[64] and mucus (Banfi et al.). CF can also be diagnosed by identification of mutations in the CFTR gene.[65]

People with CF may be listed in a disease registry that allows researchers and doctors to track health results and identify candidates for clinical trials.[66]

Couples who are pregnant or planning a pregnancy can have themselves tested for the CFTR gene mutations to determine the risk that their child will be born with cystic fibrosis. Testing is typically performed first on one or both parents and, if the risk of CF is high, testing on the fetus is performed. The American College of Obstetricians and Gynecologists (ACOG) recommends testing for couples who have a personal or close family history of CF, and they recommend that carrier testing be offered to all Caucasian couples and be made available to couples of other ethnic backgrounds.[67]

Because development of CF in the fetus requires each parent to pass on a mutated copy of the CFTR gene and because CF testing is expensive, testing is often performed initially on one parent. If testing shows that parent is a CFTR gene mutation carrier, the other parent is tested to calculate the risk that their children will have CF. CF can result from more than a thousand different mutations.[68] As of 2016 typically only the most common mutations are tested for, such as F508[68] Most commercially available tests look for 32 or fewer different mutations. If a family has a known uncommon mutation, specific screening for that mutation can be performed. Because not all known mutations are found on current tests, a negative screen does not guarantee that a child will not have CF.[69]

During pregnancy, testing can be performed on the placenta (chorionic villus sampling) or the fluid around the fetus (amniocentesis). However, chorionic villus sampling has a risk of fetal death of 1 in 100 and amniocentesis of 1 in 200;[70] a recent study has indicated this may be much lower, approximately 1 in 1,600.[71]

Economically, for carrier couples of cystic fibrosis, when comparing preimplantation genetic diagnosis (PGD) with natural conception (NC) followed by prenatal testing and abortion of affected pregnancies, PGD provides net economic benefits up to a maternal age of approximately 40 years, after which NC, prenatal testing, and abortion has higher economic benefit.[72]

While there are no cures for cystic fibrosis, there are several treatment methods. The management of cystic fibrosis has improved significantly over the past 70 years. While infants born with cystic fibrosis 70 years ago would have been unlikely to live beyond their first year, infants today are likely to live well into adulthood. Recent advances in the treatment of cystic fibrosis have meant that an individual with cystic fibrosis can live a fuller life less encumbered by their condition. The cornerstones of management are the proactive treatment of airway infection, and encouragement of good nutrition and an active lifestyle. Pulmonary rehabilitation as a management of cystic fibrosis continues throughout a person's life, and is aimed at maximizing organ function, and therefore the quality of life. At best, current treatments delay the decline in organ function. Because of the wide variation in disease symptoms, treatment typically occurs at specialist multidisciplinary centers and is tailored to the individual. Targets for therapy are the lungs, gastrointestinal tract (including pancreatic enzyme supplements), the reproductive organs (including assisted reproductive technology (ART)) and psychological support.[61]

The most consistent aspect of therapy in cystic fibrosis is limiting and treating the lung damage caused by thick mucus and infection, with the goal of maintaining quality of life. Intravenous, inhaled, and oral antibiotics are used to treat chronic and acute infections. Mechanical devices and inhalation medications are used to alter and clear the thickened mucus. These therapies, while effective, can be extremely time-consuming.

Many people with CF are on one or more antibiotics at all times, even when healthy, to prophylactically suppress infection. Antibiotics are absolutely necessary whenever pneumonia is suspected or there has been a noticeable decline in lung function, and are usually chosen based on the results of a sputum analysis and the person's past response. This prolonged therapy often necessitates hospitalization and insertion of a more permanent IV such as a peripherally inserted central catheter (PICC line) or Port-a-Cath. Inhaled therapy with antibiotics such as tobramycin, colistin, and aztreonam is often given for months at a time to improve lung function by impeding the growth of colonized bacteria.[73][74][75] Inhaled antibiotic therapy helps lung function by fighting infection, but also has significant drawbacks like development of antibiotic resistance, tinnitus and changes in the voice.[76] Oral antibiotics such as ciprofloxacin or azithromycin are given to help prevent infection or to control ongoing infection.[77] The aminoglycoside antibiotics (e.g. tobramycin) used can cause hearing loss, damage to the balance system in the inner ear or kidney problems with long-term use.[78] To prevent these side-effects, the amount of antibiotics in the blood is routinely measured and adjusted accordingly.

Several mechanical techniques are used to dislodge sputum and encourage its expectoration. In the hospital setting, chest physiotherapy (CPT) is utilized; a respiratory therapist percusses an individual's chest with his or her hands several times a day, to loosen up secretions. Devices that recreate this percussive therapy include the ThAIRapy Vest and the intrapulmonary percussive ventilator (IPV). Newer methods such as Biphasic Cuirass Ventilation, and associated clearance mode available in such devices, integrate a cough assistance phase, as well as a vibration phase for dislodging secretions. These are portable and adapted for home use.[79][needs update]Ivacaftor is an oral medication for the treatment of cystic fibrosis due to a number of specific mutations.[80][81] It improves lung function by about 10%; however, as of 2014 is expensive.[80]

Aerosolized medications that help loosen secretions include dornase alfa and hypertonic saline.[82] Dornase is a recombinant human deoxyribonuclease, which breaks down DNA in the sputum, thus decreasing its viscosity.[83]Denufosol is an investigational drug that opens an alternative chloride channel, helping to liquefy mucus.[84] It is unclear if inhaled corticosteroids are useful.[85]

As lung disease worsens, mechanical breathing support may become necessary. Individuals with CF may need to wear special masks at night that help push air into their lungs. These machines, known as bilevel positive airway pressure (BiPAP) ventilators, help prevent low blood oxygen levels during sleep. BiPAP may also be used during physical therapy to improve sputum clearance.[86][needs update] During severe illness, a tube may be placed in the throat (a procedure known as a tracheostomy) to enable breathing supported by a ventilator.

For children, preliminary studies show massage therapy may help people and their families quality of life.[87] It is unclear what effect pneumococcal vaccination has as it has not been studied as of 2014.[88]

Lung transplantation often becomes necessary for individuals with cystic fibrosis as lung function and exercise tolerance decline. Although single lung transplantation is possible in other diseases, individuals with CF must have both lungs replaced because the remaining lung might contain bacteria that could infect the transplanted lung. A pancreatic or liver transplant may be performed at the same time in order to alleviate liver disease and/or diabetes.[89] Lung transplantation is considered when lung function declines to the point where assistance from mechanical devices is required or someone's survival is threatened.[90]

Newborns with intestinal obstruction typically require surgery, whereas adults with distal intestinal obstruction syndrome typically do not. Treatment of pancreatic insufficiency by replacement of missing digestive enzymes allows the duodenum to properly absorb nutrients and vitamins that would otherwise be lost in the feces. However, the best dosage and form of pancreatic enzyme replacement is unclear, as are the risks and long-term effectiveness of this treatment.[91]

So far, no large-scale research involving the incidence of atherosclerosis and coronary heart disease in adults with cystic fibrosis has been conducted. This is likely due to the fact that the vast majority of people with cystic fibrosis do not live long enough to develop clinically significant atherosclerosis or coronary heart disease.

Diabetes is the most common non-pulmonary complication of CF. It mixes features of type 1 and type 2 diabetes, and is recognized as a distinct entity, cystic fibrosis-related diabetes (CFRD).[33][92] While oral anti-diabetic drugs are sometimes used, the only recommended treatment is the use of insulin injections or an insulin pump,[93][needs update] and, unlike in type 1 and 2 diabetes, dietary restrictions are not recommended.[33]

Development of osteoporosis can be prevented by increased intake of vitamin D and calcium, and can be treated by bisphosphonates, although adverse effects can be an issue.[94][needs update] Poor growth may be avoided by insertion of a feeding tube for increasing calories through supplemental feeds or by administration of injected growth hormone.[95]

Sinus infections are treated by prolonged courses of antibiotics. The development of nasal polyps or other chronic changes within the nasal passages may severely limit airflow through the nose, and over time reduce the person's sense of smell. Sinus surgery is often used to alleviate nasal obstruction and to limit further infections. Nasal steroids such as fluticasone are used to decrease nasal inflammation.[96]

Female infertility may be overcome by assisted reproduction technology, particularly embryo transfer techniques. Male infertility caused by absence of the vas deferens may be overcome with testicular sperm extraction (TESE), collecting sperm cells directly from the testicles. If the collected sample contains too few sperm cells to likely have a spontaneous fertilization, intracytoplasmic sperm injection can be performed.[97]Third party reproduction is also a possibility for women with CF. It is unclear if taking antioxidants affects outcomes.[98]

The prognosis for cystic fibrosis has improved due to earlier diagnosis through screening, better treatment and access to health care. In 1959, the median age of survival of children with cystic fibrosis in the United States was six months.[99] In 2010, survival is estimated to be 37 years for women and 40 for men.[100] In Canada, median survival increased from 24 years in 1982 to 47.7 in 2007.[101]

Of those with cystic fibrosis who are more than 18 years old as of 2009, 92% had graduated from high school, 67% had at least some college education, 15% were disabled and 9% were unemployed, 56% were single and 39% were married or living with a partner.[102]

Chronic illnesses can be very difficult to manage. Cystic fibrosis (CF) is a chronic illness that affects the "digestive and respiratory tracts resulting in generalized malnutrition and chronic respiratory infections".[103] The thick secretions clog the airways in the lungs, which often cause inflammation and severe lung infections.[104][105] If it is compromised, it affects the quality of life of someone with CF and their ability to complete such tasks as everyday chores. It is important for CF patients to understand the detrimental relationship that chronic illnesses place on the quality of life. According to Schmitz and Goldbeck (2006), the fact that cystic fibrosis significantly increases emotional stress on both the individual and the family, "and the necessary time-consuming daily treatment routine may have further negative effects on quality of life (QOL)".[106] However, Havermans and colleagues (2006) have shown that young outpatients with CF who have participated in the CFQ-R (Cystic Fibrosis Questionnaire-Revised) "rated some QOL domains higher than did their parents".[107] Consequently, outpatients with CF have a more positive outlook for themselves. Furthermore, there are many ways to improve the QOL in CF patients. Exercise is promoted to increase lung function. Integrating an exercise regimen into the CF patients daily routine can significantly improve the quality of life.[108] There is no definitive cure for cystic fibrosis. However, there are diverse medications used, such as mucolytics, bronchodilators, steroids, and antibiotics, that have the purpose of loosening mucus, expanding airways, decreasing inflammation, and fighting lung infections.[109]

Cystic fibrosis is the most common life-limiting autosomal recessive disease among people of European heritage.[111] In the United States, approximately 30,000 individuals have CF; most are diagnosed by six months of age. In Canada, there are approximately 4,000 people with CF.[112] Approximately 1 in 25 people of European descent, and one in 30 of Caucasian Americans,[113] is a carrier of a cystic fibrosis mutation. Although CF is less common in these groups, approximately 1 in 46 Hispanics, 1 in 65 Africans and 1 in 90 Asians carry at least one abnormal CFTR gene.[114][115] Ireland has the world's highest prevalence of cystic fibrosis, at 1:1353.[116]

Although technically a rare disease, cystic fibrosis is ranked as one of the most widespread life-shortening genetic diseases. It is most common among nations in the Western world. An exception is Finland, where only one in 80 people carry a CF mutation.[117] The World Health Organization states that "In the European Union, 1 in 20003000 newborns is found to be affected by CF".[118] In the United States, 1 in 3,500 children are born with CF.[119] In 1997, about 1 in 3,300 caucasian children in the United States was born with cystic fibrosis. In contrast, only 1 in 15,000 African American children suffered from cystic fibrosis, and in Asian Americans the rate was even lower at 1 in 32,000.[120]

Cystic fibrosis is diagnosed in males and females equally. For reasons that remain unclear, data has shown that males tend to have a longer life expectancy than females,[121][122] however recent studies suggest this gender gap may no longer exist perhaps due to improvements in health care facilities,[123][124] while a recent study from Ireland identified a link between the female hormone estrogen and worse outcomes in CF.[125]

The distribution of CF alleles varies among populations. The frequency of F508 carriers has been estimated at 1:200 in northern Sweden, 1:143 in Lithuanians, and 1:38 in Denmark. No F508 carriers were found among 171 Finns and 151 Saami people.[126] F508 does occur in Finland, but it is a minority allele there. Cystic fibrosis is known to occur in only 20 families (pedigrees) in Finland.[127]

The F508 mutation is estimated to be up to 52,000 years old.[128] Numerous hypotheses have been advanced as to why such a lethal mutation has persisted and spread in the human population. Other common autosomal recessive diseases such as sickle-cell anemia have been found to protect carriers from other diseases, a concept known as heterozygote advantage. Resistance to the following have all been proposed as possible sources of heterozygote advantage:

It is supposed that CF appeared about 3,000 BC because of migration of peoples, gene mutations, and new conditions in nourishment.[137] Although the entire clinical spectrum of CF was not recognized until the 1930s, certain aspects of CF were identified much earlier. Indeed, literature from Germany and Switzerland in the 18th century warned "Wehe dem Kind, das beim Ku auf die Stirn salzig schmekt, er ist verhext und muss bald sterbe" or "Woe to the child who tastes salty from a kiss on the brow, for he is cursed and soon must die," recognizing the association between the salt loss in CF and illness.[137]

In the 19th century, Carl von Rokitansky described a case of fetal death with meconium peritonitis, a complication of meconium ileus associated with cystic fibrosis. Meconium ileus was first described in 1905 by Karl Landsteiner.[137] In 1936, Guido Fanconi published a paper describing a connection between celiac disease, cystic fibrosis of the pancreas, and bronchiectasis.[138]

In 1938 Dorothy Hansine Andersen published an article, "Cystic Fibrosis of the Pancreas and Its Relation to Celiac Disease: a Clinical and Pathological Study," in the American Journal of Diseases of Children. She was the first to describe the characteristic cystic fibrosis of the pancreas and to correlate it with the lung and intestinal disease prominent in CF.[9] She also first hypothesized that CF was a recessive disease and first used pancreatic enzyme replacement to treat affected children. In 1952 Paul di SantAgnese discovered abnormalities in sweat electrolytes; a sweat test was developed and improved over the next decade.[139]

The first linkage between CF and another marker (Paroxonase) was found in 1985 by Hans Eiberg, indicating that only one locus exists for CF. In 1988 the first mutation for CF, F508 was discovered by Francis Collins, Lap-Chee Tsui and John R. Riordan on the seventh chromosome. Subsequent research has found over 1,000 different mutations that cause CF.

Because mutations in the CFTR gene are typically small, classical genetics techniques had been unable to accurately pinpoint the mutated gene.[140] Using protein markers, gene-linkage studies were able to map the mutation to chromosome 7. Chromosome-walking and -jumping techniques were then used to identify and sequence the gene.[141] In 1989 Lap-Chee Tsui led a team of researchers at the Hospital for Sick Children in Toronto that discovered the gene responsible for CF. Cystic fibrosis represents a classic example of how a human genetic disorder was elucidated strictly by the process of forward genetics.

Gene therapy has been explored as a potential cure for cystic fibrosis. Results from trials have shown limited success as of 2013.[142] A small study published in 2015 found a small benefit.[143]

The focus of much cystic fibrosis gene therapy research is aimed at trying to place a normal copy of the CFTR gene into affected cells. Transferring the normal CFTR gene into the affected epithelium cells would result in the production of functional CFTR in all target cells, without adverse reactions or an inflammation response. Studies have shown that to prevent the lung manifestations of cystic fibrosis, only 510% the normal amount of CFTR gene expression is needed.[144] Multiple approaches have been tested for gene transfer, such as liposomes and viral vectors in animal models and clinical trials. However, both methods were found to be relatively inefficient treatment options.[145] The main reason is that very few cells take up the vector and express the gene, so the treatment has little effect. Additionally, problems have been noted in cDNA recombination, such that the gene introduced by the treatment is rendered unusable.[146] There has been a functional repair in culture of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients.[147]

A number of small molecules that aim at compensating various mutations of the CFTR gene are under development. One approach is to develop drugs that get the ribosome to overcome the stop codon and synthesize a full-length CFTR protein. About 10% of CF result from a premature stop codon in the DNA, leading to early termination of protein synthesis and truncated proteins. These drugs target nonsense mutations such as G542X, which consists of the amino acid glycine in position 542 being replaced by a stop codon. Aminoglycoside antibiotics interfere with protein synthesis and error-correction. In some cases, they can cause the cell to overcome a premature stop codon by inserting a random amino acid, thereby allowing expression of a full-length protein.[148] The aminoglycoside gentamicin has been used to treat lung cells from CF patients in the laboratory to induce the cells to grow full-length proteins.[149] Another drug targeting nonsense mutations is ataluren, which is undergoing Phase III clinical trials as of October 2011[update].[150]

It is unclear as of 2014 if ursodeoxycholic acid is useful for those with cystic fibrosis-related liver disease.[151]

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Cystic fibrosis - Wikipedia, the free encyclopedia

What Is Gene Therapy?

Explore the what's and why's of gene therapy research, includingan in-depth look at the genetic disorder cystic fibrosis and how gene therapy could potentially be used to treat it.

Gene Delivery: Tools of the Trade

Explore the methods for delivering genes into cells.

Space Doctor

You are the doctor! Design and test gene therapy treatments with ailing aliens.

Challenges In Gene Therapy

Researchers hoping to bring gene therapy to the clinic face unique challenges.

Approaches To Gene Therapy

Beyond adding a working copy of a broken gene, gene therapy can also repair or eliminate broken genes.

Gene Therapy Successes

The future of gene therapy is bright. Learn about some of its most encouraging success stories.

Gene Therapy Case Study: Cystic Fibrosis

APA format:

Genetic Science Learning Center. (2012, December 1) Gene Therapy. Retrieved August 09, 2016, from http://learn.genetics.utah.edu/content/genetherapy/

CSE format:

Gene Therapy [Internet]. Salt Lake City (UT): Genetic Science Learning Center; 2012 [cited 2016 Aug 9] Available from http://learn.genetics.utah.edu/content/genetherapy/

Chicago format:

Genetic Science Learning Center. "Gene Therapy." Learn.Genetics. December 1, 2012. Accessed August 9, 2016. http://learn.genetics.utah.edu/content/genetherapy/.

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Gene Therapy - Learn Genetics

Editor-in-Chief: Terence R. Flotte, MD Deputy Editor, Europe: Thierry VandenDriessche, PhD Deputy Editor, U.S.: Barry J. Byrne, MD, PhD Human Gene Therapy Editor: Guangping Gao, PhD Methods Editor: Hildegard Bning, PhD Clinical Development Editor: James M. Wilson, MD, PhD

Latest Impact Factor* is 3.755 *2014 Journal Citation Reports published by Thomson Reuters, 2015

Human Gene Therapy is the premier, multidisciplinary journal covering all aspects of gene therapy. The Journal publishes in-depth coverage of DNA, RNA, and cell therapies by delivering the latest breakthroughs in research and technologies. Human Gene Therapy provides a central forum for scientific and clinical information, including ethical, legal, regulatory, social, and commercial issues, which enables the advancement and progress of therapeutic procedures leading to improved patient outcomes, and ultimately, to curing diseases.

The Journal is divided into three parts. Human Gene Therapy, the flagship, is published 12 times per year. HGT Methods, a bimonthly journal, focuses on the applications of gene therapy to product testing and development. HGT Clinical Development, a quarterly journal, serves as a venue for publishing data relevant to the regulatory review and commercial development of cell and gene therapy products.

Human Gene Therapy was voted one of the most influential journals in Biology and Medicine over the last 100 years by the Biomedical & Life Sciences Division of the Special Libraries Association.

Human Gene Therapy, HGT Methods, and HGT Clinical Development are under the editorial leadership of Editor-in-Chief Terence R. Flotte, MD, University of Massachusetts Medical School; Deput Editor Europe Thierry VandenDriessche, PhD, Free University of Brussels (VUB); Deputy Editor U.S. Barry J. Byrne, MD, PhD,Powell Gene Therapy Center, University of Florida, College of Medicine; Human Gene Therapy Editor Guangping Gao, PhD, University of Massachusetts Medical School; Methods Editor Hildegard Bning, PhD, University of Cologne; Clinical Development Editor James M. Wilson, MD, PhD,University of Pennsylvania School of Medicine, Gene Therapy Program; and other leading investigators. View the entire editorial board.

Audience: Geneticists, medical geneticists, molecular biologists, virologists, experimental researchers, and experimental medicine specialists, among others.

Human Gene Therapy and HGT Methods provide Instant Online publication 72 hours after acceptance

The views, opinions, findings, conclusions and recommendations set forth in any Journal article are solely those of the authors of those articles and do not necessarily reflect the views, policy or position of the Journal, its Publisher, its editorial staff or any affiliated Societies and should not be attributed to any of them.

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Human Gene Therapy

Gene therapy is an experimental treatment that involves inserting genetic material into your cells to give them a new function or restore a missing function, as cancer may be caused by damaged or missing genes, also known as gene mutations. Although gene therapy may be one way to overcome these changes and treat or prevent cancer, it is currently only available through clinical trials.

Cancer is caused by changes in our genes. Genes are inherited from our parents, and determine our traits and characteristics. They are made of biological molecules called deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). DNA and RNA are responsible for making proteins, which have many functions, such as helping a cell to maintain its shape or controlling its growth and division. Changes or mutations in genes can affect the proteins and may sometimes lead to diseases, such as cancer.

Gene therapy is designed to modify cancer cells at the molecular level and replace a missing or bad gene with a healthy one. The new gene is delivered to the target cell via a vector, which is usually an inactive virus or liposome, a tiny fat bubble.

Gene therapy can be done in two ways: outside (ex vivo) or inside (in vivo) your body. Ex-vivo techniques involve taking some of the cancer cells out of your body, injecting them with good genes, and then putting them back into your body. The in-vivo process requires that good genes be put directly into a tumor, which may be difficult depending on its location or if the cancer has spread. Scientists generally use two types of cells in gene therapy the tumor cells themselves and immune system cells that attack the tumors.

Researchers from Moores Cancer Center at UC San Diego Health System are studying several gene therapy techniques for breast cancer, melanoma, leukemia and pancreatic cancer.

For example, they have been integrally involved in the development of Herceptin, a targeted therapy that is proving to be effective in curing localized human epidermal growth factor receptor-2 (HER2) breast cancer. HER2 controls how cells grow, divide and repair themselves.

Researchers have also been injecting a modified herpes virus into melanoma tumors, with the intention of improving the bodys immune defenses against the disease.

Gene therapy called TNFerade Biologic involves a DNA carrier containing the gene for tumor necrosis factor-alpha, an immune system protein with potent and well-documented anti-cancer effects. TNFerade is being studied in combination with radiation therapy for first-time treatment of inoperable pancreatic cancer.

TNFerade and the herpes strategies use gene therapy to enhance the killing effect of the primary mechanism radiation in TNFerade and viral induced cell lysis, or splitting, in the herpes virus.

When will gene therapy be available? Gene therapy is only available as a cancer treatment through clinical trials.

Are there any risks associated with gene therapy clinical trials? Yes. Viral vectors might infect healthy cells as well as cancer cells, a new gene might be inserted in the wrong location in the DNA, or the transferred genes could be overexpressed and produce too much of the missing protein, causing harm. All risks for any procedure should be discussed with your doctor.

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Gene Therapy - Cancer Treatments - Moores Cancer Center ...

In Lung Cancer, Not All HER2 Alterations Are Created Equal Jan. 28, 2016 Study shows two distinct causes of HER2 activation in lung cancer: mutation of the gene and amplification of the gene. In patient samples of lung adenocarcinoma, 3 percent were found to have HER2 ... read more Dec. 12, 2015 Results from a long-term clinical trial conducted by cancer researchers show that combining radiation treatment with 'suicide gene therapy' provides a safe and effective one-two punch ... read more Gene Therapy Used to Extend Estrogen's Protective Effects on Memory Dec. 8, 2015 The hormone estrogen helps protect memory and promote a healthy brain, but this effect wanes as women age, and even estrogen replacement therapy stops working in humans after age 65. Now researchers ... read more Shrinking Tumors With an RNA Triple-Helix Hydrogel Glue Dec. 7, 2015 An efficient and effective delivery vehicle for gene therapy has been developed by researchers who have used it to shrink tumors by nearly 90 percent in a pre-clinical model of triple-negative breast ... read more Characteristics That May Increase a Breast Cancer Survivor's Risk of Developing Leukemia Following Treatment Identified Dec. 7, 2015 A new analysis indicates that certain characteristics may increase a breast cancer survivor's risk of developing leukemia after undergoing chemotherapy and/or radiation. The findings are a first ... read more Early Gene Therapy Results in Wiskott-Aldrich Syndrome Promising Dec. 6, 2015 Researchers reported promising preliminary outcomes for the first four children enrolled in a US gene therapy trial for Wiskott-Aldrich syndrome (WAS), a life-threatening genetic blood and immune ... read more Gene Therapy Restores Immunity in Children and Young Adults With Rare Immunodeficiency Dec. 6, 2015 Gene therapy can safely rebuild the immune systems of older children and young adults with X-linked severe combined immunodeficiency (SCID-X1), a rare inherited disorder that primarily affects males, ... read more MECP2 Duplication Syndrome Is Reversible, Study Suggests Nov. 25, 2015 The MECP2 Duplication Syndrome is reversible, say researchers. Importantly their study paves the way for treating duplication patients with an antisense oligonucleotide ... read more Gene Therapy: Promising Candidate for Cystic Fibrosis Treatment Nov. 16, 2015 An improved gene therapy treatment can cure mice with cystic fibrosis (CF). Cell cultures from CF patients, too, respond well to the treatment, suggest new encouraging ... read more Link Found Between Genetic Mutations, Proliferation, Immune Surveillance in Lung Cancer Nov. 11, 2015 There are four gene mutations (KRAS, TP53, STK11, and EGFR) that most commonly occur in lung cancer; however, there are limited effective therapies to target these mutations. With this in mind, ... read more Nov. 9, 2015 Genome editing techniques for blood stem cells just got better, thanks to a team of researchers. In a new article, they describe a new, more efficient way to edit genes in blood-forming or ... read more Nov. 2, 2015 Eye drops have been used to deliver the gene for a growth factor called granulocyte colony stimulating factor (G-CSF) in a mouse model of brain ischemia. The treatment led to a significant reduction ... read more Oct. 21, 2015 Delivering the hormone leptin directly to the brain through gene therapy aids weight loss without the significant side effect of bone loss, according to new ... read more New Study Explains Why You Bulk Up With Resistance Training, Not Endurance Training Oct. 20, 2015 Resistance and endurance exercises activate the same gene, PGC-1?, but the processes stimulated for the muscles to adapt depend on the exercise type. A new study offers insight into why the physical ... read more Researchers Identify Gene That Increases Risk of Sudden Death in Patients With Mild Epilepsy Oct. 15, 2015 A gene mutation that increases the risk of sudden unexpected death in epilepsy (SUDEP) in patients with mild forms of the disease has been discovered by a group of ... read more Oct. 8, 2015 Compared with direct gene injection, cell-mediated GDNF gene delivery led to considerably more pronounced preservation of myelinated fibers in the remote segments of the spinal cord (5 vs 3 mm from ... read more 'Alarm Clock' of a Leukemia-Causing Oncogene Identified Oct. 8, 2015 Mutations in DNMT3A gene cause MEIS1 activacion, triggering leukemia, a research team ... read more Oct. 5, 2015 A novel mouse model for the vision disorder Leber hereditary optic neuropathy (LHON) has been developed by researchers who have found that they can use gene therapy to improve visual function in the ... read more Genetic Polymorphism Associated With Lung Cancer Progression Oct. 5, 2015 Genetic polymorphisms associated with cancer progression lead to variations in gene expression and may serve as prognostic markers for lung cancer, researchers show. They found that in patients with ... read more New Hope for Lou: Unexplored Therapeutic Targets for ALS Sep. 3, 2015 No cures exist for amyotrophic lateral sclerosis (ALS), and the only approved therapy slows the progression by only a few months. A new study identifies a promising unexplored avenue of treatment for ... read more

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Gene Therapy News -- ScienceDaily

The mission of the Center for Gene Therapy is to investigate and employ the use of gene and cell based therapeutics for prevention and treatment of human diseases including: neuromuscular and neurodegenerative diseases, lysosomal storage disorders, ischemia and re-perfusion injury, neonatal hypertension, cancer and infectious diseases.

Learn about our areas of focus and featured research projects.

The National Institutes of Health has designated the Center for Gene Therapy as a Paul D. Wellstone Muscular Dystrophy Cooperative Research Center (MDCRC). MDCRCs promote basic, translational and clinical research and provide important resources that can be shared within the national muscle biology and neuromuscular research communities.

The MDCRC will allow Nationwide Children's researchers to further develop methods to overcome immune barriers to gene correction for Duchenne muscular dystrophy.

View the Nationwide Children's Wellstone Center page.

The Center for Gene Therapy and the Viral Vector Core are home to a Good Manufacturing Practice (GMP) production facility for manufacture of clinical-grade rAAV vectors.

View the Viral Vector Core & Clinical Manufacturing Facility site.

TheOSU and Nationwide Children's Muscle Groupbrings together investigators with diverse research interests in skeletal muscle, cardiac muscle, and neuromuscular biology.

Hosted by Kevin Flanigan, MD,"This Month in Muscular Dystrophy" podcastshighlight the latest in muscular dystrophy and other inherited neuromuscular disease research.During each podcast, authors of recent publications discuss how their work improves our understanding of inherited neuromuscular diseases, and what their work might mean for treatment of these diseases.

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Center for Gene Therapy :: The Research Institute at ...