StemCell Therapy

New step toward the treatment of myotubular myopathy gene therapy restores strength and prolongs lives in affected ... Science Daily A team of researchers in France, led by Dr. Ana Buj-Bello (Genethon/Inserm) and teams at the University of Washington and Harvard Medical School in the United States, achieved a new step towards the treatment of myotubular myopathy by gene therapy. and more »

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New step toward the treatment of myotubular myopathy gene therapy restores strength and prolongs lives in affected ... - Science Daily

Dimas Padilla, 43, of Kissimmee, is in remission from non-Hodgkin's lymphoma after receiving an experimental cancer therapy called CAR-T. Here, he poses with his wife, Dimas Padilla. NBC News

"These are patients who really are without hope," Locke said.

"Patients who at best could expect to have a one in 10 chance of having a complete disappearance of their lymphoma," he added. "So the results are really exciting and remarkable."

More than 80 percent of the 101 patients who got the treatment were still alive six months later. "Only about half the patients who (went) on this study could expect to even be alive six months after the therapy," Locke said.

Padilla is one of them. When the cancer came back most recently time, his lymph nodes were bulging. "They were so bad that they moved my vocal cords to the side and I was without my voice for almost three months," he said.

"They kept growing and my face was swelling, and I thought I was going to choke while I was sleeping."

Padilla was among the last patients enrolled in the trial.

"Once they infused the cells in my body, within two to three days all my lymph nodes started melting like ice cubes," he said.

The treatment is no cake walk. Just as with a bone marrow transplant, the patient's immune system must be damaged so that the newly engineered T-cells can do their work. That involves some harsh chemotherapy.

It's so harsh that it killed three of the patients in the trial. Padilla says he still has some memory loss from his bout with the chemo.

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"I had some fevers and I was shaking and a little bit of memory loss but it was temporary," he said. "I will say that it was pretty intense for like a week, but in my second week, second week and a half, I was starting to feel more normal. I was able to start walking and the shaking was not as bad as it was in the beginning," he said.

And when he got the news that his lymphoma was gone at least for now Padilla was delighted.

"I kissed my wife. I probably kissed the doctor," he said.

The company developing the treatment, Kite Pharma, sought Food and Drug Administration approval for the therapy on Friday.

It carries the tongue-twisting name of axicabtagene ciloleucel, and it's the first commercial CAR-T product to get into the FDA approval process.

It's far too early to say any of the patients were cured, Locke cautions. And such a difficult treatment course is really only for patients in the most desperate condition.

"The patients in this trial were really without options," he said.

But Locke is sold on the approach. "This is a revolution. It's a revolution in cancer care. This is the tip of the iceberg," he said.

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New Gene Therapy for Cancer Offers Hope to Those With No ... - NBCNews.com

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February is National Cancer Prevention Month. It's a disease that more than a million Americans are diagnosed with each year, according to the National Cancer Institute. This morning in our special series "War on Cancer," TODAY takes a look at the latest advances in the fight against this deadly disease.

Celine Ryan, a 51-year-old engineer and mother of five, was diagnosed with stage 4 colon cancer three years ago. After undergoing surgery, radiation and chemotherapy, doctors discovered cancer in her lungs seven tumors that threatened her life.

Ryan, who lives in Michigan, read about a clinical trial using gene therapy at the National Cancer Institute in Bethesda, Maryland, and decided to apply. The trial is headed up by Dr. Steven Rosenberg, a leading researcher in immunotherapy at the institute. She decided the treatment would be a birthday present to herself.

Getting into the trial wasn't simple because her tumors, though numerous, weren't large enough for the form of treatment being tested, but she was finally accepted in March 2015.

RELATED: Keytruda, the drug that helped Jimmy Carter, also can stop lung cancer

The treatment involves removing cells from a tumor your body's own cancer-fighting cells multiplying them by billions in a lab, then returning them back to your body to fight the tumor.

Celine Ryan is being referred to as an historic figure in medicine.

After spending a month in the hospital and letting the treatment run its course, six of her seven tumors had completely disappeared. The last tumor started to grow eight or nine months later and the decision was to remove it through surgery.

RELATED: 10 things I wish I knew before I was diagnosed with breast cancer

The treatment isn't widely available now, and not all patients experience the positive results Ryan had.

"Many have not responded," Rosenberg said. "But from every patient that we treat, whether... their cancers go away or not, we learn something."

Today, Celine Ryan is ten months cancer-free.

Thanks to Ryan's unusual genetic makeup, researchers were able to identify how to attack the mutation that causes common cancers. This experimental treatment may not be the solution for everyone, but for Ryan, it's meant ten months of being cancer-free.

"We can do, and are planning to do, that kind of gene therapy using the exact receptor we got from Celine's cells to treat other people," Rosenberg explained.

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The experimental gene therapy treatment that helped one woman fight cancer - Today.com

Xconomy Boston

Despite the early and in some cases stunning results produced by gene therapy treatments in handfuls of hemophilia patients, significant questions remain about their durability, safety, and how broadly theyll be used if they are ultimately shown to work. The first human data produced by Dimension Therapeutics, one of several companies developing hemophilia gene therapies, are the latest example.

Shares of Cambridge, MA-based Dimension (NASDAQ: DMTX) tumbled more than 49 percent on Tuesday on early data from a Phase 1/2 trial of DTX101, its experimental gene therapy for hemophilia B.

DTX101 boosted the levels of the blood-clotting protein Factor IX in six patients. Those on the higher of two tested doses havent needed other drugs since getting treatment. But five of the six patientsand all three on the higher of the two tested dosesalso saw a rise in liver enzyme levels, indicating an immune reaction to the gene therapy. While none of the five patients have had any safety problems, the liver enzyme spikes have caused a delay for Dimension. The company wont test an even higher dose of DTX101 in patients until it gets feedback from the FDA.

Gene therapy offers the potential of a long-lasting, if not permanent treatment for hemophilia patients, whodepending on how severe their disease ismay need frequent infusions of preventative drugs to stave off dangerous bleeds. A group of experimental gene therapies have been creeping their way forward in clinical trials, accumulating data in dribs and drabs. Spark Therapeutics (NASDAQ: ONCE) and UniQure (NASDAQ: QURE) are the furthest along in hemophilia B, while BioMarin Pharmaceutical (NASDAQ: BMRN) leads the way in the more common hemophilia A.

Each experimental therapy has shown promise helping patients produce meaningful levels of the clotting proteins Factor IX and Factor VIII, respectivelymore than 5 percent of the levels found in normal patients, which many view as the minimum bar for successover the course of a year or more. And Spark and BioMarin have seen much higher numbers than that, in some cases. But there are caveats: Those results have come in small sample sizes, and they have varied patient to patient. Data today from Dimension show the three patients on a low dose of DTX101 had roughly 3 to 4 percent of normal Factor IX levels a year after treatment. The results are earlier for those on a higher dose: 5 and 8 percent, respectively, for two patients 12 weeks post-treatment; 7 percent for a third patient 7 weeks after DTX101.

Additionally, so far, liver enzyme increases have been seen in clinical tests for each of the hemophilia gene therapies. Such increases could indicate that patients immune systems were attacking their liver cells, which are the ones that take up the therapeutic gene and churn out the new clotting protein. Theyre typically treated with a short course of immunosuppressive steroids and havent caused bad side effects so far. But in some cases theyve stifled a response to gene therapy, which is important because it means that certain gene therapies may not workor at least wont work as well as they couldfor some patients who develop neutralizing antibodies. It also means that patients who develop those antibodies wont be eligible for a second dose if the gene therapy wears off. This phenomenon reduces the potential market for the firms developing hemophilia gene therapies. Such immune responses were the impetus behind a deal Spark cut last year with Selecta Biosciences (NASDAQ: SELB), for example.

We continue to explore the therapeutic window for DTX101 as our data mature and in light of the [liver enzyme] rises that appear to be associated with a decline in [Factor IX] activity, CEO Annalisa Jenkins said in a statement.

Heres more on Dimension, and the technical differences between each of the companies developing gene therapies for hemophilia.

Ben Fidler is Xconomy's Deputy Biotechnology Editor. You can e-mail him at bfidler@xconomy.com

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Investors Sour on Data Debut For Dimension's Hemophilia Gene Therapy - Xconomy

The hottest biotechs in the field of hemophilia are stealing the show at this years edition of the EAHAD hemophilia congress in Paris.

A disorder for which no cure is available, hemophilia is caused by absent or defective genes coding for blood clotting factors, turning simple injuries intohealth risks and causing spontaneous bleeding. Researchers and companies worldwide working to improve hemophilia therapy are meeting this week in Paris for the10th Annual Congress of the European Association for Haemophilia and Allied Disorders (EAHAD).

We recently reviewed the latest advances in hemophilia, a field teeming with innovative solutions and technology.Among the most interesting presented at the congress are new results on gene therapy and RNAi, a pen to treat hemophilia and many companies fighting to reduce thedosing frequency of prophylactic therapy. On top of that, Shire has reported that current estimates of people suffering from the disease could be completely wrong

Novo Nordisk ismaking plans to use its famous insulin pens to deliver hemophilia drugs. According to astudy evaluating user experience with the pens presented at the congress, participants liked the device as it is easy to use, well designed, more portable and involving fewer steps than their current kits for hemophilia.

The ultimate goal of the Danish company is to use its FlexTouch pen to deliverconcizumab, an antibody againsttissue factor pathway inhibitor (TFPI) currently in Phase I for both hemophilia A and B.

Shire has presented a study revealing that the incidence of hemophilia could be more than three times higherthan current estimates. It also showed that only 25% of hemophiliacs receive adequate treatment. These findings might push efforts to put an end to this situation and stimulate market growth.

Shirepresented positive results from a Phase II/III trial for Adynovate (BAX 855) in children with hemophilia A. Interestingly, the company also showed early stage in vitro results for combination therapies with a biosimilar of Roches emicizumab (ACE910). It looks like the antibody, not yet in the market, already has strong competitors getting ready for when its patent expires.

Sobi, inSweden, has co-developed recombinant clotting factors with an extended half-life in partnership with Biogens spin-offBioverativ. To do so, they fuse the clotting factor to the Fc portion immunoglobulin G1 proteins.

The team has presented positive long-term safety and efficacy results forEloctatein hemophilia A andAlprolixin hemophilia B. Both are already in the market and reduce dosing frequency to weekly injections.

OPKO Biologics, in Israel, follows a strategy similar to Sobis. ItsCTP technologyextends the half-life of proteins by fusing them with theC-terminal peptide of human chorionic gonadotropin (hCG).

The company has presented data forMOD-5014(FVIIa-CTP) supporting the advance intoPhase II/IIItrials. The drug is intended for delivery twice a week, which is double of that from Sobis products.

Spark Therapeuticsis one of the leaders in the development ofgene therapy for hemophiliaanduniQures main competitor. The American company will report results from itsPhase I/IItrial forSPK-9001in hemophilia B showing sustained activity of the therapy after12 weeks, with only one reported bleeding.

Despite good results, Spark is facing strong competition from the DutchuniQure. Its gene therapyAMT-060has already shown sustained effects for at least52 weeksin a patient subpopulation. Both companies nowhavebreakthrough designation from the FDA and therace to reach the market is tight.

Sanofis partner, Alnylam, is conducting clinical trials across the UK, Switzerland and Bulgaria to test its unique RNAi technology for hemophilia. Its candidate fitusiran, which blocks antithrombin to improve clotting,is proving safe and effective inPhase I/IItrials.

This unique treatment has the potential to reduce dosing to a monthly basis and is suitable for patients with both hemophilia A and B, also including those that have developed resistanceto standard treatments.

Among the companies presenting are many others includingGenentech, Bayer and Catalyst Biosciences. The sheer number of innovative approaches under development is great news. Such a wide arrange of solutions could provide a better quality of life for hemophilia patients, each treatment suited for the particular needs of differentpatients. Especially now that, thanks to Shire, scientists know the number of patients suffering from the condition could actually be much higher.

Images from Sashkin, nobeastsofierce, Roberta Canu, Mond Duang,Art tools, LeonP,Pakpoom Nunjui /Shutterstock.com

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Gene Therapy, RNA and Pens at European Hemophilia Congress in Paris - Labiotech.eu (blog)

By the time 2-year-old Calliope Joy Carr, of Bala Cynwyd, was diagnosed with an incurable degenerative brain disease, two children with the same deadly ailment, just 20 miles away, were being offered a tenuous lifeline.

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Eli and Ella Vivian, 7- and 4-year-old siblings from Upper Providence Township, also had metachromatic leukodystrophy, a genetic disease that robs its victims, mostly children, of their motor and mental skills and, eventually, their lives. But because their symptoms were less severe than Calliope's, the Vivian children were eligible for a gene therapy clinical trial in Milan, Italy, that she was not.

Today, at 7, Calliope is bedridden, able to smile at her family and favorite TV programs and move her head slightly, but unable to speak. MLD continues to take its toll, as well, on Eli and Ella Vivian, 11 and 8. But they attend school, play, and are rambunctious in a way that Calliope has not been since three months after her diagnosis, when she spoke for the last time, saying "Daddy."

Eli and Ella "shouldn't be able to do what they are doing," said their mother, Becky Vivian. "We have hope and we are grateful, but we are realistic. It may not save their lives, just prolong it."

One in 40,000 infants is born with MLD. Now, gene therapy - the transfer of normal genes into cells to replace missing or defective ones - is engendering hope in families that their children can be more effectively treated, if not as yet cured.

Other recent developments have further boosted that optimism.

Alessandra Biffi, the physician/researcher who led the trial at Milan's San Raffaele Hospital, now directs the gene therapy program at Dana-Farber/Boston Children's Cancer and Blood Disorders Center. Further, the experimental treatment has been licensed by GlaxoSmithKline, which has major operations in Philadelphia. And the Leukodystrophy Center at Children's Hospital of Philadelphia, opened in 2015, is delivering cutting-edge care.

Andrew Shenker, vice president in GSK's rare diseases unit and project physician leader for its MLD program, cautions that the research begun in Italy in 2009 is ongoing. The pharmaceutical company expects to submit data from the trial to government regulators in 2018, after which those agencies will conduct their own reviews.

Children with MLD lack an enzyme in key cells needed for the production and maintenance of myelin, which protects nerves and facilitates the transmission of impulses within the brain. Without myelin, communication is disrupted. The patient loses basic functions, resulting in paralysis, blindness, seizures, and eventual death.

The condition is passed down from two carrier parents; any child they produce has a 1 in 4 chance of having the disease. Survival ages vary, depending on when MLD is discovered and the level of medical care. In the absence of treatment, the mean age of death for a child diagnosed at 1 to 2 years of age is 4.2 years; for those diagnosed between 4 and 14, the mean age is 17.4 years.

The most common form of treatment is stem cell therapy, but results have been "mixed" and "disappointing," Shenker said.

Other researchers are investigating treatments including enzyme replacement and gene therapy, and screening procedures to diagnose the disease at birth, said Dean Suhr, president of the Oregon-based MLD Foundation.

Results published so far on the Milan trial indicate that when treatment is administered before patients show obvious signs of the disease, the onset of symptoms is delayed, and their severity lessened.

Gene therapy appears most effective with children diagnosed before age 2 and treated before they show symptoms, Shenker said. Research on the treatment's benefit for older youngsters is ongoing.

Two children who were treated after the onset of symptoms died while participating in the trial, but their deaths were attributed to the progression of the disease, not the safety of the closely-monitored treatment, Shenker said.

Ella Vivian was one of the test cases. Because his symptoms were more advanced than hers, Eli was not part of the trial, but was treated under a "compassionate use protocol." The Inquirer published an article about the siblings in January of 2013 before the family left for Italy.

They spent six months in Milan, during which they received massive doses of chemotherapy to kill the diseased stem cells and make room for new cells containing the healthy gene to take hold. Researchers used a form of the HIV virus, minus the disease component, as a transfer agent to insert the genes.

Becky Vivian, 44, a Gymboree teacher, accompanied her children to Milan, while husband Steve stayed home with older sons Eric and Evan.

"Right now, we know they are a miracle," she said. ". . . Unfortunately, we can still see progression of the disease, albeit slowly."

Eli has difficulty standing up straight and walking, and cannot run. Ella has pain in her arms and legs, and her walking is getting slower, her writing less legible.

They have regular physical and occupational therapy, but are on no medication, their mother said. They also return to Milan every six months for checkups. In several weeks, they will be visiting Biffi in Boston for testing.

The Vivian siblings give Calliope's parents hope - if not for their daughter, then for other children with the disease and those diagnosed in the future.

Calliope, called "Cal," was diagnosed at 21/2, shortly after her parents noticed she was losing her balance on stairs.

"When we found out Cal was sick, we were really lost," said her mother, Maria Kefalas, 49, a sociology professor at Saint Joseph's University.

Three months later, Cal said her last word.

"It was like she fell off a cliff," said her father, Patrick Carr, 50, an associate professor and director of the Criminal Justice Program at Rutgers University-New Brunswick.

Cal has been in hospice care for four years, but the little girl her family knew at 2 is still there, Carr says. She loves her favorite TV shows and dolls, and smiles when brother P.J., 12, gets scolded.

Shortly after their daughter was diagnosed, Kefalas and Carr created the Calliope Joy Foundation, which has raised $300,000 - much of it by selling cupcakes - for research and patient care, including $60,000 for the Leukodystrophy Center of Excellence. The annual fund-raiser is May 6 at Lincoln Financial Field.

The charity also supports families like the Vivians, who got a donation to help with travel to Italy.

Becky Vivian says she is in a desperate race to save her children. And the family isn't letting up.

When Eli struggles with a tall chair and asks for a boost, his mother says no.

"Once we give in, it'll be time for a wheelchair. So I say, 'Eli, you've got to do it yourself.' "

kholmes@phillynews.com

610-313-8211

For information on the Calliope Joy Foundation, visit http://www.thecalliopejoyfoundation.org/

For updates on the Vivian children, visit http://www.facebook.com/Eli-Ellas-Prayer-Warriors-393482210723355/

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The promise of gene therapy for Eli and Ella, but not ...

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.

Abella, Harold. "Gene Therapy May Save Limbs." Diagnostic Imaging (May 1, 2003): 16.

Christensen R. "Cutaneous Gene TherapyAn Update." Histochemical Cell Biology (January 2001): 73-82.

"Gene Therapy Important Part of Cancer Research." Cancer Gene Therapy Week (June 30, 2003): 12.

"Initial Sequencing and Analysis of the Human Genome." Nature (February 15, 2001): 860-921.

Kingsman, Alan. "Gene Therapy Moves On." SCRIP World Pharmaceutical News (July 7, 2004): 19:ndash;21.

Nevin, Norman. "What Has Happened to Gene Therapy?" European Journal of Pediatrics (2000): S240-S242.

"New DNA Vaccine Targets Proteins Expressed in Cervical Cancer Cells." Gene Therapy Weekly (September 9, 2004): 14.

"New Research on the Progress of Gene Therapy Presented at Meeting." Obesity, Fitness & Wellness Week (July 3, 2004): 405.

Pekkanen, John. "Genetics: Medicine's Amazing Leap." Readers Digest (September 1991): 23-32.

Silverman, Jennifer, and Steve Perlstein. "Genome Project Completed." Family Practice News (May 15, 2003): 50-51.

"Study Highlights Potential Danger of Gene Therapy." Drug Week (June 20, 2003): 495.

"Study May Help Scientists Develop Safer Mthods for Gene Therapy." AIDS Weekly (June 30, 2003): 32.

Trabis, J. "With Gene Therapy, Ears Grow New Sensory Cells." Science News (June 7, 2003): 355.

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

Online Mendelian Inheritance in Man. Online genetic testing information sponsored by National Center for Biotechnology Information. http://www.ncbi.nlm.nih.gov/Omim/.

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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

Learn more about our gene therapy clinical trials

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.

Why choose Dana-Farber/Boston Childrens:

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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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Gene therapy - Wikipedia

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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.

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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

AMPK signaling, organism-specific biosystemAMPK signaling pathway, a fuel sensor and regulator, promotes ATP-producing and inhibits ATP-consuming pathways in various tissues. AMPK is a heterotrimer composed of alpha-catalytic and beta and gam...

Activation of BH3-only proteins, organism-specific biosystemThe BH3-only members act as sentinels that selectively trigger apoptosis in response to developmental cues or stress-signals like DNA damages. Widely expressed mammalian BH3-only proteins are thought...

Activation of NOXA and translocation to mitochondria, organism-specific biosystemNOXA is transactivated in a p53-dependent manner and by E2F1. Activated NOXA is translocated to mitochondria.

Activation of PUMA and translocation to mitochondria, organism-specific biosystemPuma is transactivated in a p53-dependent manner and by E2F1. Activated Puma is translocated to mitochondria.

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...

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...

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...

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 ...

Association of TriC/CCT with target proteins during biosynthesis, organism-specific biosystemTRiC has broad recognition specificities, but in the cell it interacts with only a defined set of substrates (Yam et al. 2008). Many of its substrates that are targeted during biosynthesis are conse...

Aurora A signaling, organism-specific biosystem Aurora A signaling

Autodegradation of the E3 ubiquitin ligase COP1, organism-specific biosystemCOP1 is one of several E3 ubiquitin ligases responsible for the tight regulation of p53 abundance. Following DNA damage, COP1 dissociates from p53 and is inactivated by autodegradation via a path...

BARD1 signaling events, organism-specific biosystem BARD1 signaling events

Basal cell carcinoma, organism-specific biosystemCancer of the skin is the most common cancer in Caucasians and basal cell carcinomas (BCC) account for 90% of all skin cancers. The vast majority of BCC cases are sporadic, though there is a rare fam...

Basal cell carcinoma, conserved biosystemCancer of the skin is the most common cancer in Caucasians and basal cell carcinomas (BCC) account for 90% of all skin cancers. The vast majority of BCC cases are sporadic, though there is a rare fam...

Bladder cancer, organism-specific biosystemThe urothelium covers the luminal surface of almost the entire urinary tract, extending from the renal pelvis, through the ureter and bladder, to the proximal urethra. The majority of urothelial carc...

Bladder cancer, conserved biosystemThe urothelium covers the luminal surface of almost the entire urinary tract, extending from the renal pelvis, through the ureter and bladder, to the proximal urethra. The majority of urothelial carc...

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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