StemCell Therapy

A retrovirus is any virus belonging to the viral family Retroviridae. All The genetic material in retroviruses is in the form of RNA molecules, while the genetic material of their hosts is in the form of DNA. When a retrovirus infects a host cell, it will introduce its RNA together with some enzymes into the cell. This RNA molecule from the retrovirus must produce a DNA copy from its RNA molecule before it can be considered part of the genetic material of the host cell. Retrovirus genomes commonly contain these three open reading frames that encode for proteins that can be found in the mature virus. Group-specific antigen (gag) codes for core and structural proteins of the virus, polymerase (pol) codes for reverse transcriptase, protease and integrase, and envelope (env) codes for the retroviral coat proteins (see figure 1).Figure 1. Genome organisation of retroviruses.

The process of producing a DNA copy from an RNA molecule is termed reverse transcription. It is carried out by one of the enzymes carried in the virus, called reverse transcriptase. After this DNA copy is produced and is free in the nucleus of the host cell, it must be incorporated into the genome of the host cell. That is, it must be inserted into the large DNA molecules in the cell (the chromosomes). This process is done by another enzyme carried in the virus called integrase (see figure 2).

Now that the genetic material of the virus is incorporated and has become part of the genetic material of the host cell, we can say that the host cell is now modified to contain a new gene. If this host cell divides later, its descendants will all contain the new genes. Sometimes the genes of the retrovirus do not express their information immediately.

Retroviral vectors are created by removal op the retroviral gag, pol, and env genes. These are replaced by the therapeutic gene. In order to produce vector particles a packaging cell is essential. Packaging cell lines provide all the viral proteins required for capsid production and the virion maturation of the vector. These packaging cell lines have been made so that they contain the gag, pol and env genes. Early packaging cell lines contained replication competent retroviral genomes and a single recombination event between this genome and the retroviral DNA vector could result in the production of a wild type virus. Following insertion of the desired gene into in the retroviral DNA vector, and maintainance of the proper packaging cell line, it is now a simple matter to prepare retroviral vectors (see figure 3).

One of the problems of gene therapy using retroviruses is that the integrase enzyme can insert the genetic material of the virus in any arbitrary position in the genome of the host. If genetic material happens to be inserted in the middle of one of the original genes of the host cell, this gene will be disrupted (insertional mutagenesis). If the gene happens to be one regulating cell division, uncontrolled cell division (i.e., cancer) can occur. This problem has recently begun to be addressed by utilizing zinc finger nucleases or by including certain sequences such as the beta-globin locus control region to direct the site of integration to specific chromosomal sites.

Gene therapy trials to treat severe combined immunodeficiency (SCID) were halted or restricted in the USA when leukemia was reported in three of eleven patients treated in the French X-linked SCID (X-SCID) gene therapy trial. Ten X-SCID patients treated in England have not presented leukemia to date and have had similar success in immune reconstitution. Gene therapy trials to treat SCID due to deficiency of the Adenosine Deaminase (ADA) enzyme continue with relative success in the USA, Italy and Japan.

As a reaction to the adverse events in the French X-SCID gene therapy trial, the Recombinant DNA Advisory Committee (RAC) sent a letter to Principal Investigators Conveying RAC Recommendations in 2003. In addition, the RAC published conclusions and recommendations of the RAC Gene Transfer Safety Symposium in 2005. A joint working party of the Gene Therapy Advisory Committee and the Committee on Safety of Medicines (CSM) in the UK lead to the publication of an updated recommendations of the GTAC/CSM working party on retroviruses in 2005.

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Gene Therapy Retrovirus Vectors Explained

Gene therapy utilizes the delivery of DNA into cells, which can be accomplished by several methods, summarized below. The two major classes of methods are those that use recombinant viruses (sometimes called biological nanoparticles or viral vectors) and those that use naked DNA or DNA complexes (non-viral methods).

All viruses bind to their hosts and introduce their genetic material into the host cell as part of their replication cycle. This genetic material contains basic 'instructions' of how to produce more copies of these viruses, hacking the body's normal production machinery to serve the needs of the virus. The host cell will carry out these instructions and produce additional copies of the virus, leading to more and more cells becoming infected. Some types of viruses insert their genome into the host's cytoplasm, but do not actually enter the cell. Others penetrate the cell membrane disguised as protein molecules and enter the cell.

There are two main types of virus infection: lytic and lysogenic. Shortly after inserting its DNA, viruses of the lytic cycle quickly produce more viruses, burst from the cell and infect more cells. Lysogenic viruses integrate their DNA into the DNA of the host cell and may live in the body for many years before responding to a trigger. The virus reproduces as the cell does and does not inflict bodily harm until it is triggered. The trigger releases the DNA from that of the host and employs it to create new viruses.

The genetic material in retroviruses is in the form of RNA molecules, while the genetic material of their hosts is in the form of DNA. When a retrovirus infects a host cell, it will introduce its RNA together with some enzymes, namely reverse transcriptase and integrase, into the cell. This RNA molecule from the retrovirus must produce a DNA copy from its RNA molecule before it can be integrated into the genetic material of the host cell. The process of producing a DNA copy from an RNA molecule is termed reverse transcription. It is carried out by one of the enzymes carried in the virus, called reverse transcriptase. After this DNA copy is produced and is free in the nucleus of the host cell, it must be incorporated into the genome of the host cell. That is, it must be inserted into the large DNA molecules in the cell (the chromosomes). This process is done by another enzyme carried in the virus called integrase.

Now that the genetic material of the virus has been inserted, it can be said that the host cell has been modified to contain new genes. If this host cell divides later, its descendants will all contain the new genes. Sometimes the genes of the retrovirus do not express their information immediately.

One of the problems of gene therapy using retroviruses is that the integrase enzyme can insert the genetic material of the virus into any arbitrary position in the genome of the host; it randomly inserts the genetic material into a chromosome. If genetic material happens to be inserted in the middle of one of the original genes of the host cell, this gene will be disrupted (insertional mutagenesis). If the gene happens to be one regulating cell division, uncontrolled cell division (i.e., cancer) can occur. This problem has recently begun to be addressed by utilizing zinc finger nucleases[1] or by including certain sequences such as the beta-globin locus control region to direct the site of integration to specific chromosomal sites.

Gene therapy trials using retroviral vectors to treat X-linked severe combined immunodeficiency (X-SCID) represent the most successful application of gene therapy to date. More than twenty patients have been treated in France and Britain, with a high rate of immune system reconstitution observed. Similar trials were restricted or halted in the USA when leukemia was reported in patients treated in the French X-SCID gene therapy trial.[citation needed] To date, four children in the French trial and one in the British trial have developed leukemia as a result of insertional mutagenesis by the retroviral vector. All but one of these children responded well to conventional anti-leukemia treatment. Gene therapy trials to treat SCID due to deficiency of the Adenosine Deaminase (ADA) enzyme (one form of SCID)[2] continue with relative success in the USA, Britain, Ireland, Italy and Japan.

Adenoviruses are viruses that carry their genetic material in the form of double-stranded DNA. They cause respiratory, intestinal, and eye infections in humans (especially the common cold). When these viruses infect a host cell, they introduce their DNA molecule into the host. The genetic material of the adenoviruses is not incorporated (transient) into the host cell's genetic material. The DNA molecule is left free in the nucleus of the host cell, and the instructions in this extra DNA molecule are transcribed just like any other gene. The only difference is that these extra genes are not replicated when the cell is about to undergo cell division so the descendants of that cell will not have the extra gene. As a result, treatment with the adenovirus will require readministration in a growing cell population although the absence of integration into the host cell's genome should prevent the type of cancer seen in the SCID trials. This vector system has been promoted for treating cancer and indeed the first gene therapy product to be licensed to treat cancer, Gendicine, is an adenovirus. Gendicine, an adenoviral p53-based gene therapy was approved by the Chinese food and drug regulators in 2003 for treatment of head and neck cancer. Advexin, a similar gene therapy approach from Introgen, was turned down by the US Food and Drug Administration (FDA) in 2008.

Concerns about the safety of adenovirus vectors were raised after the 1999 death of Jesse Gelsinger while participating in a gene therapy trial. Since then, work using adenovirus vectors has focused on genetically crippled versions of the virus.

The viral vectors described above have natural host cell populations that they infect most efficiently. Retroviruses have limited natural host cell ranges, and although adenovirus and adeno-associated virus are able to infect a relatively broader range of cells efficiently, some cell types are refractory to infection by these viruses as well. Attachment to and entry into a susceptible cell is mediated by the protein envelope on the surface of a virus. Retroviruses and adeno-associated viruses have a single protein coating their membrane, while adenoviruses are coated with both an envelope protein and fibers that extend away from the surface of the virus. The envelope proteins on each of these viruses bind to cell-surface molecules such as heparin sulfate, which localizes them upon the surface of the potential host, as well as with the specific protein receptor that either induces entry-promoting structural changes in the viral protein, or localizes the virus in endosomes wherein acidification of the lumen induces this refolding of the viral coat. In either case, entry into potential host cells requires a favorable interaction between a protein on the surface of the virus and a protein on the surface of the cell. For the purposes of gene therapy, one might either want to limit or expand the range of cells susceptible to transduction by a gene therapy vector. To this end, many vectors have been developed in which the endogenous viral envelope proteins have been replaced by either envelope proteins from other viruses, or by chimeric proteins. Such chimera would consist of those parts of the viral protein necessary for incorporation into the virion as well as sequences meant to interact with specific host cell proteins. Viruses in which the envelope proteins have been replaced as described are referred to as pseudotyped viruses. For example, the most popular retroviral vector for use in gene therapy trials has been the lentivirus Simian immunodeficiency virus coated with the envelope proteins, G-protein, from Vesicular stomatitis virus. This vector is referred to as VSV G-pseudotyped lentivirus, and infects an almost universal set of cells. This tropism is characteristic of the VSV G-protein with which this vector is coated. Many attempts have been made to limit the tropism of viral vectors to one or a few host cell populations. This advance would allow for the systemic administration of a relatively small amount of vector. The potential for off-target cell modification would be limited, and many concerns from the medical community would be alleviated. Most attempts to limit tropism have used chimeric envelope proteins bearing antibody fragments. These vectors show great promise for the development of "magic bullet" gene therapies.

A replication-competent vector called ONYX-015 is used in replicating tumor cells. It was found that in the absence of the E1B-55Kd viral protein, adenovirus caused very rapid apoptosis of infected, p53(+) cells, and this results in dramatically reduced virus progeny and no subsequent spread. Apoptosis was mainly the result of the ability of EIA to inactivate p300. In p53(-) cells, deletion of E1B 55kd has no consequence in terms of apoptosis, and viral replication is similar to that of wild-type virus, resulting in massive killing of cells.

A replication-defective vector deletes some essential genes. These deleted genes are still necessary in the body so they are replaced with either a helper virus or a DNA molecule.

[3]

Replication-defective vectors always contain a transfer construct. The transfer construct carries the gene to be transduced or transgene. The transfer construct also carries the sequences which are necessary for the general functioning of the viral genome: packaging sequence, repeats for replication and, when needed, priming of reverse transcription. These are denominated cis-acting elements, because they need to be on the same piece of DNA as the viral genome and the gene of interest. Trans-acting elements are viral elements, which can be encoded on a different DNA molecule. For example, the viral structural proteins can be expressed from a different genetic element than the viral genome.

[3]

The Herpes simplex virus is a human neurotropic virus. This is mostly examined for gene transfer in the nervous system. The wild type HSV-1 virus is able to infect neurons and evade the host immune response, but may still become reactivated and produce a lytic cycle of viral replication. Therefore, it is typical to use mutant strains of HSV-1 that are deficient in their ability to replicate. Though the latent virus is not transcriptionally apparent, it does possess neuron specific promoters that can continue to function normally[further explanation needed]. Antibodies to HSV-1 are common in humans, however complications due to herpes infection are somewhat rare.[4] Caution for rare cases of encephalitis must be taken and this provides some rationale to using HSV-2 as a viral vector as it generally has tropism for neuronal cells innervating the urogenital area of the body and could then spare the host of severe pathology in the brain.

Non-viral methods present certain advantages over viral methods, with simple large scale production and low host immunogenicity being just two. Previously, low levels of transfection and expression of the gene held non-viral methods at a disadvantage; however, recent advances in vector technology have yielded molecules and techniques with transfection efficiencies similar to those of viruses.[5]

This is the simplest method of non-viral transfection. Clinical trials carried out of intramuscular injection of a naked DNA plasmid have occurred with some success; however, the expression has been very low in comparison to other methods of transfection. In addition to trials with plasmids, there have been trials with naked PCR product, which have had similar or greater success. Cellular uptake of naked DNA is generally inefficient. Research efforts focusing on improving the efficiency of naked DNA uptake have yielded several novel methods, such as electroporation, sonoporation, and the use of a "gene gun", which shoots DNA coated gold particles into the cell using high pressure gas.[6]

Electroporation is a method that uses short pulses of high voltage to carry DNA across the cell membrane. This shock is thought to cause temporary formation of pores in the cell membrane, allowing DNA molecules to pass through. Electroporation is generally efficient and works across a broad range of cell types. However, a high rate of cell death following electroporation has limited its use, including clinical applications.

More recently a newer method of electroporation, termed electron-avalanche transfection, has been used in gene therapy experiments. By using a high-voltage plasma discharge, DNA was efficiently delivered following very short (microsecond) pulses. Compared to electroporation, the technique resulted in greatly increased efficiency and less cellular damage.

The use of particle bombardment, or the gene gun, is another physical method of DNA transfection. In this technique, DNA is coated onto gold particles and loaded into a device which generates a force to achieve penetration of the DNA into the cells, leaving the gold behind on a "stopping" disk.

Sonoporation uses ultrasonic frequencies to deliver DNA into cells. The process of acoustic cavitation is thought to disrupt the cell membrane and allow DNA to move into cells.

In a method termed magnetofection, DNA is complexed to magnetic particles, and a magnet is placed underneath the tissue culture dish to bring DNA complexes into contact with a cell monolayer.

Hydrodynamic delivery involves rapid injection of a high volume of a solution into vasculature (such as into the inferior vena cava, bile duct, or tail vein). The solution contains molecules that are to be inserted into cells, such as DNA plasmids or siRNA, and transfer of these molecules into cells is assisted by the elevated hydrostatic pressure caused by the high volume of injected solution.[7][8][9]

The use of synthetic oligonucleotides in gene therapy is to deactivate the genes involved in the disease process. There are several methods by which this is achieved. One strategy uses antisense specific to the target gene to disrupt the transcription of the faulty gene. Another uses small molecules of RNA called siRNA to signal the cell to cleave specific unique sequences in the mRNA transcript of the faulty gene, disrupting translation of the faulty mRNA, and therefore expression of the gene. A further strategy uses double stranded oligodeoxynucleotides as a decoy for the transcription factors that are required to activate the transcription of the target gene. The transcription factors bind to the decoys instead of the promoter of the faulty gene, which reduces the transcription of the target gene, lowering expression. Additionally, single stranded DNA oligonucleotides have been used to direct a single base change within a mutant gene. The oligonucleotide is designed to anneal with complementarity to the target gene with the exception of a central base, the target base, which serves as the template base for repair. This technique is referred to as oligonucleotide mediated gene repair, targeted gene repair, or targeted nucleotide alteration.

To improve the delivery of the new DNA into the cell, the DNA must be protected from damage and positively charged. Initially, anionic and neutral lipids were used for the construction of lipoplexes for synthetic vectors. However, in spite of the facts that there is little toxicity associated with them, that they are compatible with body fluids and that there was a possibility of adapting them to be tissue specific; they are complicated and time consuming to produce so attention was turned to the cationic versions.

Cationic lipids, due to their positive charge, were first used to condense negatively charged DNA molecules so as to facilitate the encapsulation of DNA into liposomes. Later it was found that the use of cationic lipids significantly enhanced the stability of lipoplexes. Also as a result of their charge, cationic liposomes interact with the cell membrane, endocytosis was widely believed as the major route by which cells uptake lipoplexes. Endosomes are formed as the results of endocytosis, however, if genes can not be released into cytoplasm by breaking the membrane of endosome, they will be sent to lysosomes where all DNA will be destroyed before they could achieve their functions. It was also found that although cationic lipids themselves could condense and encapsulate DNA into liposomes, the transfection efficiency is very low due to the lack of ability in terms of endosomal escaping. However, when helper lipids (usually electroneutral lipids, such as DOPE) were added to form lipoplexes, much higher transfection efficiency was observed. Later on, it was figured out that certain lipids have the ability to destabilize endosomal membranes so as to facilitate the escape of DNA from endosome, therefore those lipids are called fusogenic lipids. Although cationic liposomes have been widely used as an alternative for gene delivery vectors, a dose dependent toxicity of cationic lipids were also observed which could limit their therapeutic usages.

The most common use of lipoplexes has been in gene transfer into cancer cells, where the supplied genes have activated tumor suppressor control genes in the cell and decrease the activity of oncogenes. Recent studies have shown lipoplexes to be useful in transfecting respiratory epithelial cells.

Polymersomes are synthetic versions of liposomes (vesicles with a lipid bilayer), made of amphiphilic block copolymers. They can encapsulate either hydrophilic or hydrophobic contents and can be used to deliver cargo such as DNA, proteins, or drugs to cells. Advantages of polymersomes over liposomes include greater stability, mechanical strength, blood circulation time, and storage capacity.[10][11][12]

Complexes of polymers with DNA are called polyplexes. Most polyplexes consist of cationic polymers and their fabrication is based on self-assembly by ionic interactions. One important difference between the methods of action of polyplexes and lipoplexes is that polyplexes cannot directly release their DNA load into the cytoplasm. As a result, co-transfection with endosome-lytic agents such as inactivated adenovirus was required to facilitate nanoparticle escape from the endocytic vesicle made during particle uptake. However, a better understanding of the mechanisms by which DNA can escape from endolysosomal pathway, i.e. proton sponge effect,[13] has triggered new polymer synthesis strategies such as incorporation of protonable residues in polymer backbone and has revitalized research on polycation-based systems.[14]

Due to their low toxicity, high loading capacity, and ease of fabrication, polycationic nanocarriers demonstrate great promise compared to their rivals such as viral vectors which show high immunogenicity and potential carcinogenicity, and lipid-based vectors which cause dose dependence toxicity. Polyethyleneimine[15] and chitosan are among the polymeric carriers that have been extensively studies for development of gene delivery therapeutics. Other polycationic carriers such as poly(beta-amino esters)[16] and polyphosphoramidate[17] are being added to the library of potential gene carriers. In addition to the variety of polymers and copolymers, the ease of controlling the size, shape, surface chemistry of these polymeric nano-carriers gives them an edge in targeting capability and taking advantage of enhanced permeability and retention effect.[18]

A dendrimer is a highly branched macromolecule with a spherical shape. The surface of the particle may be functionalized in many ways and many of the properties of the resulting construct are determined by its surface.

In particular it is possible to construct a cationic dendrimer, i.e. one with a positive surface charge. When in the presence of genetic material such as DNA or RNA, charge complimentarity leads to a temporary association of the nucleic acid with the cationic dendrimer. On reaching its destination the dendrimer-nucleic acid complex is then taken into the cell via endocytosis.

In recent years the benchmark for transfection agents has been cationic lipids. Limitations of these competing reagents have been reported to include: the lack of ability to transfect some cell types, the lack of robust active targeting capabilities, incompatibility with animal models, and toxicity. Dendrimers offer robust covalent construction and extreme control over molecule structure, and therefore size. Together these give compelling advantages compared to existing approaches.

Producing dendrimers has historically been a slow and expensive process consisting of numerous slow reactions, an obstacle that severely curtailed their commercial development. The Michigan-based company Dendritic Nanotechnologies discovered a method to produce dendrimers using kinetically driven chemistry, a process that not only reduced cost by a magnitude of three, but also cut reaction time from over a month to several days. These new "Priostar" dendrimers can be specifically constructed to carry a DNA or RNA payload that transfects cells at a high efficiency with little or no toxicity.[citation needed]

Inorganic nanoparticles, such as gold, silica, iron oxide (ex. magnetofection) and calcium phosphates have been shown to be capable of gene delivery.[19] Some of the benefits of inorganic vectors is in their storage stability, low manufacturing cost and often time, low immunogenicity, and resistance to microbial attack. Nanosized materials less than 100nm have been shown to efficiently trap the DNA or RNA and allows its escape from the endosome without degradation. Inorganics have also been shown to exhibit improved in vitro transfection for attached cell lines due to their increased density and preferential location on the base of the culture dish. Quantum dots have also been used successfully and permits the coupling of gene therapy with a stable fluorescence marker.

Cell-penetrating peptides (CPPs), also known as peptide transduction domains (PTDs), are short peptides (< 40 amino acids) that efficiently pass through cell membranes while being covalently or non-covalently bound to various molecules, thus facilitating these molecules entry into cells. Cell entry occurs primarily by endocytosis but other entry mechanisms also exist. Examples of cargo molecules of CPPs include nucleic acids, liposomes, and drugs of low molecular weight.[20][21]

CPP cargo can be directed into specific cell organelles by incorporating localization sequences into CPP sequences. For example, nuclear localization sequences are commonly used to guide CPP cargo into the nucleus.[22] For guidance into mitochondria, a mitochondrial targeting sequence can be used; this method is used in protofection (a technique that allows for foreign mitochondrial DNA to be inserted into cells' mitochondria).[23][24]

Due to every method of gene transfer having shortcomings, there have been some hybrid methods developed that combine two or more techniques. Virosomes are one example; they combine liposomes with an inactivated HIV or influenza virus. This has been shown to have more efficient gene transfer in respiratory epithelial cells than either viral or liposomal methods alone. Other methods involve mixing other viral vectors with cationic lipids or hybridising viruses.

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Vectors in gene therapy - Wikipedia

A panel of cancer experts Wednesday recommended approval of what could become the first gene therapy available in the U.S.

The Food and Drug Administration advisory panel voted 10-0 in favor of an advanced leukemia treatment developed by the University of Pennsylvania and Novartis Corp. The FDA usually follows recommendations of its expert panels, but isn't obligated to do so.

The therapy could be the first of a wave of treatments custom-made to target a patient's cancer. Called CAR-T, it involves removing immune cells from a patients' blood, reprogramming them to create an army of cells that can zero in on and destroy cancer cells, and injecting them back into the patient.

"This is a major advance," said panel member Dr. Malcolm A. Smith of the National Cancer Institute. He said the treatment is "ushering in a new era."

The vote came after lengthy discussion and impassioned pleas from the fathers of two young patients whose lives were saved by the therapy. The one-time leukemia treatment would be for children and young adults with the most common form of childhood cancer, known as ALL.

"Our daughter was going to die and now she leads a normal life," said Tom Whitehead, of Philipsburg, Pennsylvania. His daughter Emily, now 12, was the first child to receive the experimental therapy, five years ago. "We believe when this treatment is approved, it will save thousands of children's lives around the world."

After decades of setbacks and disappointments in efforts to fix, replace, or change genes to cure diseases, several companies are near the finish line in a race to bring CAR-T and other types of gene therapy to patients. Kite Pharma also has a CAR-T therapy in FDA review and Juno Therapeutics and others are in late stages of testing.

Novartis is seeking approval to use the treatment for patients aged 3 to 25 with a blood cancer called acute lymphoblastic leukemia whose disease has spread or failed to respond to standard treatment. That happens to more than 600 patients in the U.S. each year. At that point, they have limited options all more toxic than the CAR-T therapy and survival chances are slim. ALL accounts for a quarter of all cancers in children under age 15.

In a key test, results were far better than chemotherapy and even newer types of cancer drugs. Of the 52 patients whose results were analyzed, 83 percent had complete remission, meaning their cancer vanished. Most patients suffered serious side effects but nearly all recovered.

CAR-T therapy starts with filtering key immune cells called T cells from a patient's blood. In a lab, a gene is then inserted into the T cells that prompts them to grow a receptor that targets a special marker found on some blood cancers. Millions of copies of the new T cells are grown in the lab and then injected into the patient's bloodstream where they can seek out and destroy cancer cells. Doctors call it a "living drug" permanently altered cells that continue to multiply in the body into an army to fight the disease.

During the patient testing, the whole process took about 16 weeks, which can be too long a wait for some desperately ill patients, the FDA advisers noted during the meeting in Silver Spring, Maryland. Drug company officials said they can now produce a treatment and get it to a patient in about three weeks.

Novartis said in a statement that it has long believed CAR-T therapy could "change the cancer treatment paradigm."

The cost of CAR-T therapy is likely to be hundreds of thousands of dollars, but it's only given once. Typically, cancer patients take one or more drugs until they stop working, then switch to other drugs, so treatment and side effects can go on for years.

The treatment's short-term side effects, including fever and hallucinations, are often intense as the body's revved up immune system goes on the attack. The long-term side effects of the treatment are unknown. It's also unclear if patients whose cancer goes into remission will be cured or will have their cancer return eventually. The FDA panel recommended that patients who get the treatment be monitored for 15 years.

Other biotech and pharmaceutical companies are developing types of gene therapy to treat solid cancers and rare gene-linked diseases. A few products have been approved elsewhere one for head and neck cancer in China in 2004 and two in Europe, most recently GlaxoSmithKline's Strimvelis. That was approved last year for a deadly condition called severe combined immunodeficiency and launched with a $670,000 price tag.

UniQure's Glybera was approved for a rare enzyme disorder. It was used only once in five years, likely due to its $1 million-plus price tag, so uniQure is pulling it from the market.

Follow Linda A. Johnson at https://twitter.com/LindaJonPharma

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FDA advisers endorse what could be 1st US gene therapy - ABC News

An experimental therapy for treating children and young adults with advanced leukemia could be the first gene therapy approved in the United States, potentially opening the door to a wave of treatments custom-made to target a patients cancer.

A panel of cancer experts that advises the federal Food and Drug Administration panel is holding a hearing Wednesday to discuss the treatment developed by the University of Pennsylvania and Novartis Corp.

The drugmaker is seeking approval to use the one-time treatment for children and young adults.

Called CAR-T, it involves removing immune cells from patients blood, genetically altering them in effect, reprogramming them to create an army of attack cells and then putting them back in the patients to fight these blood cancers.

The therapy could pave the way for other individualized, custom-made cancer treatments. Dr. Carl June, the Penn scientist who led the development of this immunotherapy, told the Washington Post it would be a true living drug.

The panel is reviewing the safety, effectiveness and production of the treatment. It will vote on whether to recommend FDA approval. The federal agency typically goes along with the recommendations of its advisory panels.

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FDA cancer advisers consider what would be first gene therapy in US - Chicago Sun-Times

South Koreas Ministry of Food and Drug Safety said today that it has approved the countrys first gene therapy for osteoarthritis, the lead product candidate of a Maryland-based regenerative medicine company.

Invossa-K Inj. was developed by Maryland-based TissueGene, whose Korean licensee, Kolon Life Sciences, won approval for the injectable treatment. According to the company, Invossa is a first-in-class cell-mediated gene therapy designed to treat moderate (Kellgren and Lawrence grade 3) knee osteoarthritis through regeneration of cartilage.

Invossa uses allogeneic human cartilage cells engineered to express transforming growth factor TGF-1. TissueGenes platform technology involves transducing the cells with a retroviral vector engineered to express TGF-1 at a specific therapeutic level and duration of time.

The modified cell lines are further selected and screened for cellular expression characteristics intended to minimize patient immune response to the injected cellsthen mixed with unmodified cells to create cartilage regeneration via Invossa, as well as bone, disc, and nerve regeneration through the companys other product candidates.

Invossa is designed for a single injection directly into the knee joint, allowing the cells to induce repair and regeneration of tissue by secreting therapeutic growth factors. The gene therapyincluded in GENs recent roundup of Top Trends in Tissue Engineeringis an alternative to surgery for arthritis patients, according to Kolon.

Kolon has said injection of Invossa has been shown in Phase III trials in Korea to ease the symptoms of about 84% of patientswhile 88% of U.S. patients treated with the gene therapy in Phase 2 trials reported improved symptoms for up to two years.

Invossa is being assessed in a Phase III trial in the U.S. after TissueGene and the FDA came to agreement on a Special Protocol Assessment (SPA) for the study. The company is seeking agency approval for the gene therapy as the first disease-modifying osteoarthritis drug (DMOAD).

Kolon has also inked an exclusive licensing and development agreement with Mitsubishi Tanabe Pharma to market the drug in Japan. Under that deal, Mitsubishi Tanabe agreed to pay approximately $24 million upfront plus up to $410 million in payments tied to achieving development, regulatory, and commercial milestones, plus double-digit sales royalties.

In Korea, Mundipharma plans to market and distribute Invossa to general and semiprivate hospitals, while Kolon focuses on general practitioners, under an agreement announced April 11.

With the Korean drug ministrys approval, Invossa became the 29th South Koreandeveloped novel therapy approved by the countrys drug regulatory agencyand one of only four cell gene therapies to have ever been approved globally. The others were approved to treat immunodeficiency diseases, genetic disorders, and cancer.

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South Korea OKs First-in-Class Gene Therapy for Osteoarthritis - Genetic Engineering & Biotechnology News

(Reuters) - The U.S. Food and Drug Administration will ask a panel of advisors to focus on the safety of Novartis AG's experimental gene therapy drug when it meets to review the product on Wednesday.

The keenly anticipated preliminary review of the leukemia treatment, posted on the FDA's website on Monday, comes two days ahead of the advisory panel meeting, which will discuss the drug and vote on whether the benefits exceed the risks.

If approved, the drug, tisagenlecleucel, would be the first gene therapy to be approved in the United States. The FDA is not obliged to follow the recommendations of its advisors but typically does so.

The panel's decision could have significant implications not only for Novartis but for companies making similar drugs, including Kite Pharma Inc. Juno Therapeutics Inc and bluebird bio Inc.

The drugs use a new technology known as CAR-T, or chimeric antigen receptor T-cell therapy, which harnesses the body's own immune cells to recognize and attack malignant cells.

If approved they are expected to cost up to $500,000 and generate billions of dollars for their developers. Success would also help advance a cancer-fighting technique that scientists have been trying to perfect for decades.

Novartis is applying for approval in the first instance to treat B-cell acute lymphoblastic leukemia (ALL), the most common type of childhood cancer in the United States.

A clinical trial showed that 83 percent of patients who had relapsed or failed chemotherapy achieved complete or partial remission three months post infusion. Patients with ALL who fail chemotherapy typically have only a 16 to 30 percent chance of survival.

The FDA said it is not asking the panel to focus on whether the drug works, as it successfully met the main goal of the clinical trial. The panel will be asked only to focus on the short-term and long-term safety risks.

About half the patients experienced a serious complication known as cytokine release syndrome (CRS) which occurs when the body's immune system goes into overdrive. Doctors were able to manage the condition and it caused no patient deaths.

The FDA also raised concerns that the drug may cause secondary malignancies to occur and said long-term safety monitoring may be needed to address this concern.

Novartis is also testing its drug in diffuse large b-cell Lymphoma (DLBCL), the most common form of non-Hodgkin lymphoma, as is Kite. Part of the competitive landscape will include which company is best able to manufacture its drugs efficiently and reliably.

Reporting by Toni Clarke in Washington; Editing by Nick Zieminski

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FDA panel to focus on safety of Novartis gene therapy drug - Reuters

Dimas Padilla, 43, of Kissimmee, is in remission from non-Hodgkins lymphoma after receiving an experimental cancer therapy called CAR-T. Here, he poses with his wife, Johanna Padilla. NBC News

Its worked well in patients who had no other options after going through rounds of chemo and bone marrow transplants. More than one-third of patients who got the treatment 39 percent are tumor-free nine months later, researchers will tell a meeting of the American Association for Cancer Research that starts this weekend.

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 patients immune system must be damaged so that the newly engineered T-cells can do their work. That involves some harsh chemotherapy.

Its 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.

Related:

Cancer Moonshot Panel Says Focus on Immune Therapies

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 its the first commercial CAR-T product to get into the FDA approval process.

Its 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. Its a revolution in cancer care. This is the tip of the iceberg, he said.

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New Gene Therapy Shows Promise for Dire Cancer Cases - 41 NBC News

Testing mares and stallions can help ensure foals are born free or at low risk of some genetic diseases.

Photo: iStock

Genetics refers to the study of genes and the way traits of conditions are passed down from one generation to another. Genomics, on the other hand, describes the study of all genes (the genome) including interactions of genes with each other and the environment. Although much of the genetic and genomic research done in Thoroughbreds is applied to racing performance, the full breadth of application of genetic and genomic research goes beyond that of faster horses.

Genetics and genomics allow for a more complete understanding of both simple and complex diseases. From a genetic perspective, simple is a term used to describe a disease that follows a single gene pattern of inheritance. These diseases are controlled by one gene, with other genes and outside factors having very little influence (i.e., the presence of the gene = disease). Diseases inherited this way are typically qualitative, where an animal either has the disease or it doesnt (i.e., lethal white foal syndrome).

Complex diseases, on the other hand, are usually controlled by not one, but many different genes and are often affected by environmental factors, such as nutrition and living conditions (e.g., cervical vertebral stenotic myelopathy, or wobbler syndrome). This combination of both genetic and environmental factors results in complex or multifactorial diseases. Basically, three different scenarios determine the manifestation of a complex disease:

As a result, complex genetic diseases can be extremely difficult to diagnose early and/or prevent using tradition methods such as pedigree analyses and veterinary evaluations. In some instances, a simple disease might even be classified as complex based on the inability of epidemiological studies and pedigree analyses to find common factors among cases.

Hydrocephalus, for example, is a developmental disorder that often results in stillbirth of foals and dystocia (difficult birth) in dams. Possible causes of the defect in horses could not be prove based on field data and pedigree analyses suggested the disorder to be complex. With this in mind, a genomic scan of 82 horses (13 cases and 69 controls) was performed and a small section of the genome was identified. Genomic sequencing was then performed on 10 horses (four cases and six controls) and the genetic cause of the disorder was pinpointed.

Figure 1

Two copies of a mutation that changes a "C" nucleotide to a "T" nucleotide results in hydrocephalus.

Photo: Equine Disease Quarterly

Ultimately, two copies of a mutation that changed a C nucleotide to a T nucleotide (Figure 1) resulted in the disorder. Although previously believed to be a complex disease, genetic and genomic methods were able to prove that the disorder was, in fact, simple, leading to the development of a genetic test that can help breeders avoid the disorder.

It is important to note the difference between a genetic test of a simple disease, such as hydrocephalus, and a genetic test for a complex disease (e.g., osteochondrosis). Genetic tests for simple diseases can confirm or rule out a genetic condition; however, genetic tests for complex diseases only help to determine an individuals chance of developing a genetic disorderan important distinction when genetic tests are used to help make breeding decisions. In either scenario, genetics and genomics in Thoroughbreds have far-reaching potential beyond that of breeding and selecting faster horses.

Understanding diseases caused by a single gene as well as complex diseases caused by multiple genes and the environment can lead to early diagnosis and targeted treatments. While the list of reasons a racehorse never reaches its potential might seem endless, genetics and genomics provide an opportunity to cross certain disorders off that list, thereby helping to eliminate or reduce the occurrence of those diseases.

CONTACTBrandon D. Velie, MS, PhDbrandon.velie@slu.seSwedish University of Agricultural Sciences Department of Animal Breeding and Genetics, Uppsala, Sweden

This is an excerpt from Equine Disease Quarterly, funded by underwriters at Lloyds, London.

Original post:
Genetics and Genomics in Racing: Speed Isn't Everything - TheHorse.com

Investment to the tune of US$25m has been announced by Hendrix Genetics in the form of a new commercial turkey hatchery in South Dakota, United States.

The hatchery will provide up to 30m day-old Hybrid poults and lead to the addition of 100 new temporary and permanent jobs at the site at Beresford.

The new hatchery will have the capacity for 35m hatching eggs and will be fitted with cutting edge equipment to ensure the highest biosecurity and poult quality.

Dave Libertini, Hendrix Genetics managing director, said: The new hatchery allows us to continue to deliver on our core focus of providing top quality genetics that match the needs of the market and our customers. Photo: ANP / Justin Sullivan

It is part of a substantial investment plan by Hendrix, which includes new hatcheries, egg production facilities and a modern transportation fleet and follows previous investments in grandparent facilities in Kansas and Nebraska.

Dave Libertini, Hendrix Genetics managing director, said: The new hatchery allows us to continue to deliver on our core focus of providing top quality genetics that match the needs of the market and our customers. This is a critical component of our plan to modernise the commercial turkey distribution infrastructure in the USA.

Matt McCready, Hendrix Genetics director of business development, added the hatchery would join the network of owned, aligned and contracted hatchery capacity set up to supply the strong demand for Hybrid genetics in the USA.

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Hendrix Genetics announce new US turkey hatchery investment - Poultry World (subscription)

ABS Global announced July 12 the launch of NuEra Genetics, a new brand that encompasses all proprietary ABS beef breeding programs, evaluations, and indexes in order to deliver differentiated and superior terminal genetics for beef supply chain profitability.

ABS said NuEra Genetics symbolizes the next chapter in the history of ABS beef genetics and a new era of ABS beef genetic improvement.

This new brand provides customers access to continuous genetic improvement and a wider array of tailored evaluations and indexes that deliver genetic progress and profit faster, ABS said.

How will customers benefit? According to ABS, the answer is found in the NuEra Genetics tagline: Efficiency. Profitability. Sustainability. With NuEra, the goal is to optimize the customers efficiency, leading to greater profitability, and ultimately allowing for a sustainable system.

The new brand will strive to:

Customers should look for new products to be released under the NuEra Genetics brand in the coming months. Such products include proprietary indexes tailored to specific customer needs, making it easier for customers to select the most efficient and profitable genetics. In the long-term, NuEra will consistently deliver robust genetic improvement, year-on-year, to our customers, raising the bar of what is possible for them to achieve.

As we see dairymen focus the adoption of sexed genetics on their high-ranking females, NuEra Genetics will provide these producers with elite beef genetics for those lower-ranking cows, adding a significant revenue stream to their businesses, said Nate Zwald, chief operating officer of ABS Globals dairy division.

Jerry Thompson, chief operating officer of ABS Globals beef division, said NuEra Genetics has the potential to add significant value to the beef industry globally. Weve only really just scratched the surface and creating our own genetics to drive customer profitability will help us tap into many areas of growth opportunity.

Excerpt from:
ABS Global launches NuEra Genetics beef program - Feedstuffs

Afsaneh Khetrapal | July 12, 2017 | News Medical

The term tongue twisting comprises rolling, folding, rotating, adjusting, and turning of the tongueAll aspects of a person are in some way influenced by genetics. Likewise, the tongue structure or its movement is controlled by ones respective gene patternTongue twisting is not a genetic disease or disorder, but a unique activity by a person using his tongue.

The early history of tongue genetics stated that the ability of tongue twisting is due to the influence of traitsThe tongue rolling ability occurs due to the influence of a dominant allele of the gene. A person who has either one or two copies of the dominant allele will be able to twist their tongue. In the case that a person is born with two recessive alleles, they cannot twist their tongue. In most cases, parents with a twisting-tongue ability can give birth to non-tongue twisters, and vice versa.

After a long-drawn out struggle, geneticists and researchers have finally proved that tongue twisting does not occur by genetic transformation. Genetic inheritance has only a minimal role to play in tongue twisting skills.

The GLP aggregated and excerpted this blog/article to reflect the diversity of news, opinion, and analysis. Read full, original post:Genetics of Tongue Twisting

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Genetics of tongue twisting: Why some people do it while others can't - Genetic Literacy Project

Ah, summer vacation. The time of year when high school students laze on the beach, sleep in and stay up late binge watching their favorite TV shows.

But Greenwood native Emelee Guest is doing none of that. Her days have been occupied looking for mutations on Cullin-4B, a gene that has been linked to intellectual disabilities.

Ive been working with gene CUL4B and basically studying mutation E900X, which is basically a truncating mutation and Ive been studying the effects that a treatment called G-418 has on the mutation, is how the 17-year-old describes her work.

An incoming senior at the Governors School for Science and Mathematics in Hartsville, the 17-year-old is taking part in an intensive six-week research experience at the Greenwood Genetic Center under the guidance of Dr. Anand Srivastava, associate director for the facilitys Center for Molecular Studies.

Guest, who spent her freshman and sophomore years at Greenwood High School, said she was drawn to the field of genetics because she has relatives living with cystic fibrosis and epilepsy.

Part of my motivation is to help them. Ive watched them grow up with them, Guest said.

Guest is in elite company. Just one of 12 specialized, residential high schools in the country, the Governors School for Science and Mathematics which has an acceptance process offers more than 50 STEM classes with college and graduate-level opportunities and AP classes that enable students to earn multiple credits before starting their high education careers.

At my old school, we would sit there and learn, but there would be no application of it and there, we have labs once a week and they have more biology electives, Guest said. People say, get there, get anywhere, and its the hardest two years of your life.

More from this section (Story continues below)

Srivastava, whos taken summer interns from the Governors School for more than 10 years, said the arrangement is mutually beneficial for research institutions like the Genetic Center, which gets access to the next generation of scientists while providing real-world experience for students.

They are very committed, they desire to learn because they have some goals, Srivastava said. We try to design a project that is part of some ongoing project and they get to work with somebody in my lab, which allows them to learn and become independent.

Guest, who is undecided between pursuing a career in genetics and ecology, said the practical skills of working at summer internship in a high pressure laboratory setting are impactful.

I dont think I could have guessed what it was going to be like, just because I havent a lot of experience just some little things in class and its nothing like the real thing, she said. Its a little stressful sometimes because its a lot of small things that have to correctly but once you get used to it, its really exciting.

Contact staff writer Adam Benson at 864-943-5650 or on Twitter @ABensonIJ.

Original post:
Greenwood native doing high-level genetics work in hometown - Index-Journal

Written by AZoNanoJul 10 2017

The Koch Institute for Integrative Cancer Research at MIT will soon be reaching the first anniversary of the launch of the Marble Center for Cancer Nanomedicine, founded through a generous gift from Kathy and Curt Marble 63.

The Marble Center for Cancer Nanomedicines faculty is made up of Koch Institute members who are committed to fighting cancer with nanomedicine through research, education, and collaboration. Top row (l-r) Sangeeta Bhatia, director; Daniel Anderson; and Angela Belcher. Bottom row: Paula Hammond; Darrell Irvine; and Robert Langer. (Photo: Koch Institute Marble Center for Cancer Nanomedicine)

Bringing together leading Koch Institute faculty members and their teams, the Marble Center for Cancer Nanomedicine focuses on huge challenges in cancer detection, treatment and monitoring that can profit from the latest physics and biology of the nanoscale.

These challenges include spotting cancer earlier than present techniques allow, harnessing the immune system to combat cancer even as it progresses, using therapeutic insights from cancer biology to design therapies for formerly undruggable targets, integrating current drugs for synergistic action, and developing tools for more accurate diagnosis and improved surgical intervention.

Koch Institute member Sangeeta N. Bhatia, the John J. and Dorothy Wilson, Professor of Health Sciences and Technology and Electrical Engineering and Computer Science, serves as the Inaugural Director of the center.

A major goal for research at the Marble Center is to leverage the collaborative culture at the Koch Institute to use nanotechnology to improve cancer diagnosis and care in patients around the world.

Sangeeta N. Bhatia, Koch Institute Member

Transforming nanomedicine

The Marble Center joins MITs larger efforts at the forefront of discovery and advancement to solve the critical global challenge that is cancer. The concept of convergence the combination of the life and physical sciences with engineering is a trademark of MIT, the founding principle of the Koch Institute, and at the heart of the Marble Centers mission.

The center galvanizes the MIT cancer research community in efforts to use nanomedicine as a translational platform for cancer care. Its transformative by applying these emerging technologies to push the boundaries of cancer detection, treatment, and monitoring and translational by promoting their development and application in the clinic.

Tyler Jacks, Director of the Koch Institute and a David H. Koch Professor of Biology

The centers faculty six renowned MIT Professors and Koch Institute Members are committed to combating cancer with nanomedicine through research, education and partnership. They are, Sangeeta Bhatia (director), the John J. and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science; Daniel G. Anderson, the Samuel A. Goldblith Professor of Applied Biology in the Department of Chemical Engineering and the Institute for Medical Engineering and Science; Angela M. Belcher, the James Mason Crafts Professor in the departments of Biological Engineering and Materials Science and Engineering; Paula T. Hammond, the David H. Koch Professor of Engineering and head of the Department of Chemical Engineering; Darrell J. Irvine, Professor in the departments of Biological Engineering and Materials Science and Engineering; and Robert S. Langer, the David H. Koch Institute Professor.

Extending their partnership within the walls of the Institute, members of the Marble Center profit greatly from the support of the Peterson (1957) Nanotechnology Materials Core Facility in the Koch Institutes Robert A. Swanson (1969) Biotechnology Center. The Peterson Facilitys array of technological resources and know-how is unparalleled in the United States, and gives members of the center and of the Koch Institute, a distinctive advantage in the development and application of materials and technologies at the nanoscale.

Looking ahead

The Marble Center made the most of its first year, and has provided backing for advanced research projects including theranostic nanoparticles that can both detect and treat cancers, real-time imaging of interactions between cancer and immune cells to properly understand reaction to cancer immunotherapies, and delivery technologies for a number of powerful RNA-based therapeutics capable of engaging specific cancer targets with precision.

As part of its efforts to help adopt a multifaceted science and engineering research force, the center has offered fellowship support for trainees as well as valuable opportunities for scientific exchange, mentorship and professional development.

Promoting wider engagement, the Marble Center serves as a bridge to a broad network of nanomedicine resources, linking its members to MIT.nano, other Nanotechnology Researchers, and Clinical Partners across Boston and beyond. The center has also set up a scientific advisory board, whose members come from leading clinical and academic centers around the country, and will assist in shaping the centers future programs and continued development.

As the Marble Center enters another year of partnerships and innovation, there is a new landmark in sight for 2018. Nanomedicine has been chosen as the main theme for the Koch Institutes 17th Annual Cancer Research Symposium. The event is scheduled for June 15th, 2018, and will bring together national domain experts, providing a perfect forum for Marble Center members to share the discoveries and progresses made during its sophomore year.

Having next years KI Annual Symposium dedicated to nanomedicine will be a wonderful way to further expose the cancer research community to the power of doing science at the nanoscale. The interdisciplinary approach has the power to accelerate new ideas at this exciting interface of nanotechnology and medicine.

Sangeeta N. Bhatia, Koch Institute Member

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Koch Institute's Marble Center for Cancer Nanomedicine Brings Together Renowned Faculty to Combat Cancer - AZoNano

This summer, the Koch Institute for Integrative Cancer Research at MIT marks the first anniversary of the launch of the Marble Center for Cancer Nanomedicine, established through a generous gift from Kathy and Curt Marble 63.

Bringing together leading Koch Institute faculty members and their teams, the Marble Center for Cancer Nanomedicine focuses on grand challenges in cancer detection, treatment, and monitoring that can benefit from the emerging biology and physics of the nanoscale.

These challenges include detecting cancer earlier than existing methods allow, harnessing the immune system to fight cancer even as it evolves, using therapeutic insights from cancer biology to design therapies for previously undruggable targets, combining existing drugs for synergistic action, and creating tools for more accurate diagnosis and better surgical intervention.

Koch Institute member Sangeeta N. Bhatia, the John J. and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science, serves as the inaugural director for the center.

A major goal for research at the Marble Center is to leverage the collaborative culture at the Koch Institute to use nanotechnology to improve cancer diagnosis and care in patients around the world, Bhatia says.

Transforming nanomedicine

The Marble Center joins MITs broader efforts at the forefront of discovery and innovation to solve the urgent global challenge that is cancer. The concept of convergence the blending of the life and physical sciences with engineering is a hallmark of MIT, the founding principle of the Koch Institute, and at the heart of the Marble Centers mission.

The center galvanizes the MIT cancer research community in efforts to use nanomedicine as a translational platform for cancer care, says Tyler Jacks, director of the Koch Institute and a David H. Koch Professor of Biology. Its transformative by applying these emerging technologies to push the boundaries of cancer detection, treatment, and monitoring and translational by promoting their development and application in the clinic.

The centers faculty six prominent MIT professors and Koch Institute members are committed to fighting cancer with nanomedicine through research, education, and collaboration. They are:

Sangeeta Bhatia (director), the John J. and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science;

Daniel G. Anderson, the Samuel A. Goldblith Professor of Applied Biology in the Department of Chemical Engineering and the Institute for Medical Engineering and Science;

Angela M. Belcher, the James Mason Crafts Professor in the departments of Biological Engineering and Materials Science and Engineering;

Paula T. Hammond, the David H. Koch Professor of Engineering and head of the Department of Chemical Engineering;

Darrell J. Irvine, professor in the departments of Biological Engineering and Materials Science and Engineering; and

Robert S. Langer, the David H. Koch Institute Professor.

Extending their collaboration within the walls of the Institute, Marble Center members benefit greatly from the support of the Peterson (1957) Nanotechnology Materials Core Facility in the Koch Institutes Robert A. Swanson (1969) Biotechnology Center. The Peterson Facilitys array of technological resources and expertise is unmatched in the United States, and gives members of the center, and of the Koch Institute, a distinct advantage in the development and application of nanoscale materials and technologies.

Looking ahead

The Marble Center has wasted no time getting up to speed in its first year, and has provided support for innovative research projects including theranostic nanoparticles that can both detect and treat cancers, real-time imaging of interactions between cancer and immune cells to better understand response to cancer immunotherapies, and delivery technologies for several powerful RNA-based therapeutics able to engage specific cancer targets with precision.

As part of its efforts to help foster a multifaceted science and engineering research force, the center has provided fellowship support for trainees as well as valuable opportunities for mentorship, scientific exchange, and professional development.

Promotingbroader engagement, the Marble Center serves as a bridge to a wide network of nanomedicine resources, connecting its members to MIT.nano, other nanotechnology researchers, and clinical collaborators across Boston and beyond. The center has also convened a scientific advisory board, whose members hail from leading academic and clinical centers around the country, and will help shape the centers future programs and continued expansion.

As the Marble Center begins another year of collaborations and innovation, there is a new milestone in sight for 2018.Nanomedicine has been selected as the central theme for the Koch Institutes 17th Annual Cancer Research Symposium. Scheduled for June 15, 2018, the event will bring together national leaders in the field, providing an ideal forum for Marble Center members to share the discoveries and advancements made during its sophomore year.

Having next years KI Annual Symposium dedicated to nanomedicine will be a wonderful way to further expose the cancer research community to the power of doing science at the nanoscale, Bhatia says. The interdisciplinary approach has the power to accelerate new ideas at this exciting interface of nanotechnology and medicine.

To learn more about the people and projects of the Koch Institute Marble Center for Cancer Nanomedicine, visit nanomedicine.mit.edu.

Continue reading here:
Converging on cancer at the nanoscale | MIT News - The MIT Tech

The department wanted nanotechnology to benefit the poor, so it directed funding towards pro-poor initiatives by prioritising research into diseases such as HIV and tuberculosis (TB). However, many less prominent diseases received proportionately more attention. In an unpublished report by the Mapungubwe Institute, researchers found that Parkinsons disease accounts for 2% of nanomedicine research, but is only 0.04% of South African disability-adjusted life years. In addition to Parkinsons, South African scholars study malaria, hepatitis B and Alzheimers in greater proportion than their disability-adjusted life years.

On the other hand, HIV/AIDS is severely understudied. HIV/AIDS accounts for 40% of SAs disability-adjusted life years but represents only 4% of South African nanomedicine research. The gross mismatch between R&D and the needs of South Africans shows that the interests of researchers can be at odds with the needs of the community.

We believe this mismatch is the symptom of global trends in medical R&D and the challenging economics of developing medicines that help the poor. Pharmaceutical companies have little desire to research diseases such as malaria, TB and HIV/AIDS because it will be difficult for them to recoup their R&D costs from medicine sales. In contrast, there is a robust market for cancer and Parkinsons disease medicines and they are, therefore, willing to invest in R&D in these fields.

As a consequence, well-targeted state intervention is needed to encourage R&D on diseases that do not have a market.

In a provocative book titled The Entrepreneurial State, Mariana Mazzucato provides examples of cases in which the state has inevitably been a lead investor and risk-taker in capitalist economies through "mission-oriented" investments and policies.

They include key technologies such as the internet, nanotechnologies, microbiology and drug discovery technologies, where the state played a leading role in achieving the necessary technological breakthroughs.

The state can risk funding initial R&D in areas that have no clear market but that push the bounds of science. An outstanding example is the iPhone all the key technologies behind it, such as the touchscreen, the internet and microprocessors, were funded by the state. The Obama administration also provided a direct $465m loan to Tesla Motors to build its model S.

The state should undertake risky investment to find solutions for its critical medicine research and drug discovery. The focus of private pharma is to focus on less innovative drugs, and private venture capitalists enter only once the real risk has been absorbed by the state.

Bill Gates said the key element to getting a breakthrough is more basic research, and that requires the government to take the lead. Only when that research is pointing towards a product, can we expect the private sector to kick in.

The government should play a leading role as an "entrepreneurial" investor and reap some of the financial rewards over time by retaining ownership of a small proportion of the intellectual property created.

Rather than succumb to its preassigned role as a "market fixer", the governments role should include resource mobilisation and setting the conditions for widespread market commercialisation.

It is time for SA to ask: what is it that the public and private sectors can do together to tackle the dire healthcare situation?

There is a great need for science and politics to combine efforts. A diverse set of governance actors, programmes, instruments and influences are needed by each form of new technology.

These recommendations will not immediately solve all of SAs health problems, but would put the country in a better position to improve its health-innovation system and the wellbeing of its people.

Woodson is assistant professor at Stony Brook University and Perrot is an independent researcher.

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State can cure skewed disease research - BusinessLIVE - Business Day (registration)

Priorities soon may change, because new research published in the journal Environmental Science & Technology finds that common household dust can cause fat cells to accumulate more triglycerides, or fat.

The problematic components are endocrine-disrupting chemicals (EDCs). These are synthetic or naturally occurring compounds that can interfere with, or mimic, a persons hormones. Since they are in products like frequently used flame retardants, dust from EDCs tends to be prevalent.

It is not clear at this time which items contribute most to EDC concentrations measured indust, senior author Heather Stapleton of Duke University said. The use of many of these chemicals is considered Confidential Business Information (CBI) and is often not disclosed to the public.

What we do know, she added, is that furniture, insulation, electronics, and other building components contain these chemicals, and are likely sources for thedust.

RELATED:Household Dust Packed With Thousands of Microbes

Stapleton, lead author Christopher Kassotis, and co-author Kate Hoffman made the dust-fat connection after analyzing samples of indoor dust from 11 homes in North Carolina. Extracts from seven of the eleven samples triggered the accumulation of triglycerides, a type of fat, in a lab dish. Extracts from nine samples did even more. They spurred the cells to divide, resulting in a larger amount of precursor fat cells.

Among the forty-four individual common house dust contaminants tested chemicals such as phthalates, parabens, pesticides, and phenolics three exhibited the strongest fat-producing effects. They were the pesticide pyraclostrobin, the flame retardant TBPDP, and the commonly used plasticizer DBP.

Prior research on animals suggests that early life exposure to some EDCs can cause weight gain later in life. Some scientists even refer to these ubiquitous chemicals now as obesogens.

Stapleton and other researchers believe that EDCs may interact with fetus stem cells and other developing tissues, causing them to develop in a different way than what would normally occur.

For example, she said, an EDC might change the way an adipocyte (fat cell) functions in adulthood. This might make it easier for these cells to accumulate lipids and lead to greater weight gain in one individual with high exposure during perinatal periods, compared to someone that was not exposed during the perinatal period. However, more research is really needed to understand these long-term effects.

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Common Household Dust Might Be Causing People to Gain Weight - Seeker

Fillers those line plumping and wrinkle-reducing injections (usually of hyaluronic acid) have gotten increasingly popular over the past several years. The quick, in-office procedure can deliver addictively good results without all the scariness that comes with full-blown cosmetic surgeries. But thats not to say fillers dont have serious risks... like blindness, apparently.

A recent study published in the Journal of the American Society of Plastic Surgeons, looked at nine patients in South Korea who experienced blindness from fillers after receiving facial injections of hyaluronic acid.

One of the rare risks of having filler injections performed is that the filler material itself can get into and block a blood vessel, Joshua Zeichner, M.D., director of cosmetic and clinical research in dermatology at Mount Sinai Hospital in New York City, tells Allure. If that happens, the results can be devastating.Here's what goes down: The blockage can prevent the delivery of oxygen and other nutrients, which could have major consequences. If the skin is affected, scarring can develop. If the eyes are affected, it can result in blindness, Zeichner adds.

Naturally, the case study is scary enough to make you rethink booking that filler appointment. But before you totally freak out, heres what you need to know about the real risks concerning blindness from fillers.

First of all, this is super rare. For all the procedures involving fillers (about 2.6 million people got the needle last year alone, according to the American Society of Plastic Surgeons), theres only been a handful of reported cases of blindness. In the event that after a filler injection, you experience any significant, sharp pain, if the skin develops a purple, lacy, or dusky appearance make sure to call your doctor immediately, Zeichner says. Hyaluronic acid fillers can be dissolved, so if theres an issue, the faster you can do that, the better your chances of avoiding a serious outcome.

Secondly, where you get the filler matters. Certain areas are more at risk than others, Sejal Shah, M.D., a board-certified dermatologist in New York, tells Allure. The highest risk areas are the area between the eyebrows, the nose, and the nasal region. In those areas, neurotoxin injections (aka Botox or Dysport) might be the safer choice, adds Zeichner.

Finally, technique is key, so make sure you see someone who knows their stuff. Many of us do not inject fillers in high-risk areas and actually pull back on the plunger of the syringe before injecting to make sure that the needle is not placed within a blood vessel, Zeichner says. To ensure youre getting the best care, "make sure you are seeing a well-trained, board-certified dermatologist or plastic surgeon, who is thoroughly educated in facial anatomy and techniques for injecting different types of fillers, adds Shah. These experts will also be able to deal with any adverse effects ASAP.

The bottom line? Every medical procedure including the seemingly innocuous facial perk up you can get with a quick injection has risks. So make sure you know what they are going in. Before resorting to the needle, talk to your dermatologist about any weird side effects you might be at risk for and inject accordingly.

For more on fillers:

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Great, Well Apparently Facial Fillers Can Make You Go Blind - Allure Magazine

With only a 48-hour window of opportunity, how do you keep a child from going blind when there is a lack of eye surgeons with proper training? Thats where telemedicine technology and eye specialists come together.

Childrens Hospital Los Angeles is the largest pediatric multispecialty medical group in the United States. Children from around the world can receive specialized care from 564 physicians in any of 32 specialties and 31 other areas of complex conditions.

Recently, one group within Childrens Hospital Los Angeles looked at the rate of infant blindness in Armenia which was three times the rate of the U.S. and other Western countries and asked, How can we help? How could the medical group eliminate preventable blindness in Armenia and neighboring rural areas? And how could the medical group educate doctors in third-world countries about complex blinding diseases in a cost-effective manner without compromising care?

[Also:VA, Air Force forge telehealth partnership for critically ill patients]

Thomas Lee, MD, joined the Armenia EyeCare Project at Childrens Hospital Los Angeles. He and a team of doctors traveled to Armenia to provide assessment, care and programming, and the need to train remote care teams became clear: There were not enough surgeons available with the specialized knowledge required to provide life-changing eye surgeries.

Another critical issue was that some of these sight-saving surgeries for premature infants with certain retinal conditions must take place within 48 hours of birth. The lack of trained surgeons meant many infants might miss their opportunity.

[Also:eClinicalWorks adds telehealth feature to mobile app]

So SADA Systems, a Microsoft partner, built a telemedicine system using Microsoft technology especially for Lee to reach out from L.A. to Armenia to stop infants from going blind.

Skype for Business along with a Polycom codec allowed us to be present virtually during the operation, Lee said. One of the primary obstacles to training surgeons in developing countries is the difficulty in getting the expertise to the trainee to properly supervise them during their actual operations. Historically this has required the expert to travel to the remote country and then assist the doctor directly.

These medical missions are very time-consuming, and unfortunately often need to be arranged months in advance, a period of time many patients do not have, Lee said.

By having a remote platform available, we were able to provide the supervision needed in a timely fashion for the patient without requiring the expert to disrupt their own practice, he explained.

Various elements of the telemedicine technology enabled Lee and team members to succeed at this medical procedure.

Historically, we have been limited in how the video signal is transmitted and brokered, Lee said. Encoding and compressing the signal has often relied on software compression performed in the OR before being placed on the wire. This results in compression and motion artifacts that cause signal degradation making it unusable from a medical standpoint.

Some of the more affordable hardware systems resulted in latency of up to 60 seconds as the streaming system would buffer the video before broadcasting to the remote expert, Lee explained. A dedicated hardware codec at both ends would solve this issue but required the remote expert to be at the hospital where the codec is present, and since Armenia was 12 time zones away, this posed a specific challenge, he added.

What was unique and novel about this solution was that SADA Systems reconfigured a Polycom codec to log directly on to Microsoft Skype for Business, he explained. The hardware compression resulted in a high-definition and high-frame-rate signal with none of the artifacts we had seen previously. Because this was being brokered by Skype for Business, the remote expert could simply log onto the video conference from home using a standard web browser.

What was even more important was that the signal could be multicast to multiple experts around the world. This was a fundamental change.

Where historically we could only have one expert training a surgeon, either in person or remotely, Skype for Business allowed us to crowdsource the surgical training to experts all over the world, Lee said. This changes the rules of the game. Experience that would normally take a trainee months to acquire through different experts can now be addressed in one operation. This really alters how we can approach a global problem through a disruptive platform to benefit children all over the world.

So how important is telemedicine technology to the future of healthcare? Very, Lee said.

In healthcare today, we are facing a crisis not just in cost but more importantly in access, he said. Telemedicine will allow us to address both of these issues by allowing subspecialists to partner with other providers in an efficient manner that can both increase access and reduce costs. The challenge is how to complete the proof of concept and then roll out the larger platform.

Twitter:@SiwickiHealthITEmail the writer: bill.siwicki@himssmedia.com

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LA medical group uses telemedicine to fight child blindness in Armenia - Healthcare IT News

From the dawn of electronics, people have been tryingto merge electronics with our bodies in order to improve conditions thatcurrently have no cure andto go beyond our limits. The US Defense Advanced Research Projects Agency (DARPA) is now ready to back that up with big bucks.

DARPA has announced it plans to spend $65 million to create a brain-computer interface, the core goal of the Neural Engineering System Design program. The program will last for four years and willfund six different research teams. These scientists will work on LEDs that can be used to restore vision, a system to understand speech, and a holographic microscope to detect neural activity.

While these are all part of an exciting plan, it is important to remember just how ambitious it is. Even if the technology developed is as successful as one might hope, it would take years to perform clinical tests to guarantee that the tech is safe and reliable. DARPA wants the team to create commercially viable applications, but there are many obstacles to overcome.

The general idea is to create different versions of the same basic technology, an interface that can translate the electrochemical signals into electronic impulses and vice versa. Only in such a manner would it be possible to control potential sensory devices.

The researchers will tryto create a brain implant thatis at most a cubic centimeter (about two nickels stuck back to back) in volume. The volume requirements are sensible but not groundbreaking. Previous studies have shown implants that are minimally invasive.

The chip will have to be able to connect and communicate withup to a million neurons, and while that sounds impressive, we need to remember that the average human has about 86 billion of them.

Still, a technology that can interface with our neural electrochemistry can have a huge impact, even if it only interacts with a (relatively) tiny fraction of neurons. The implant can help bridge nerve connections, which means it might help people that have lost limb function or have a spinal injury.

Obviously, this is early work, but it is promising that research groups are committed to a tech that might make life easier for millions of people.

See the article here:
DARPA Aims At Curing Blindness And Other Conditions With Bioelectronic Interface - IFLScience

When Maureen and Jay Neitz adopted an adorable, fluffy black puppy in the late 1980s, they had no idea how important she would be in making new discoveries about vision.

They were just looking for a dog who was size-appropriate for the small apartment they lived in as UC Santa Barbara PhD candidates. Eventually, the teacup Poodle they named Retina helped the couple prove that dogs see much more than just black and white, and that dogs color vision is similar to that of the 8 percent of the human population who are red-green colorblind.

Ten million Americans, most of them male, are affected with red-green colorblindness, a genetic trait carried on the X chromosome. People with this condition cant clearly see the difference between red and green. They often mistake green for white and red for brown or dark gray.

Colorblindness might not seem like a serious disability, but it causes unexpected, and sometimes tragic, problems for humans. For example, airline pilots must be able to differentiate between colors, which someone with red-green colorblindness cant reliably do. Color vision is, of course, crucial in being able to discern if a traffic light is red or green. According to Don Peters, a consultant to the biotech industry who has red/green colorblindness, Sodium vapor lights look a lot like red stoplights to me. Its confusing to drive in an area with these lights, especially at night. As a child, he had difficulties with color-related tasks: I can still hear my teacher asking me why I colored the tree red. I couldnt tell the difference.

Colorblind people miss a lot of detail that people with normal color vision take for granted: they might not see the lines on a map, or lettering printed in colors that seem bright to those with normal vision but blend in for them. This can be dangerous when reading traffic signs or medication labels. Jay Neitz pointed out that children who are colorblind often have trouble in school, and can be mistakenly diagnosed with learning disabilities or ADHD; in spite of these potential problems, schools do not test students color vision.

The Neitzes established that dogs see shades of yellow, blue and gray. Other colors, such as red and green, appear faded or indistinct. Jay Neitz had an aha moment when Retina could not find her orange ball in a green lawn. Sometimes the ball was right in front of her, but she would sniff around in the grass, trying to find it by smell. We realized that she simply couldnt see it, even though it was obvious to us, he said.

As UC Santa Barbara post-docs with degrees in biochemistry, molecular biology and biopsychology, the couple had access to a lab in which they could set up a testing area. I realized that I had the opportunity to find out, once and for all, what kind of color vision dogs really have. Jay built an apparatus that placed dogs in front of a screen with three lit panels. He trained the dogs to touch the screen with their noses when they saw a different shade. If the dog got it right, she would receive a cheese-flavored dog treat. In order to get the dog to touch the screen, Jay used peanut butter as an incentive. Once the dog mastered that part of the test, Jay no longer used the peanut butter.

Right away, Maureen and Jay discovered that, like people, dogs were good at figuring out shortcuts to getting a treat. In addition, About 30 percent of the time, the dog made a lucky guess, according to Maureen. The dogs attention spans were short, and on more than a few days, they just didnt feel like doing the tests. It took six months per dog to train them, Maureen said. In addition to Retina, the Neitzes used two Italian Greyhounds; like Poodles, they are small, intelligent, easily trained dogs. The dogs were treated very well, Maureen said. We had the utmost concern for their welfare.

In 1989, Jay Neitz co-authored Color vision in the dog, which was published in the journal Visual Neuroscience; the research paper confirmed that dogs do, indeed see more than black and white. That led to a years-long search for a cure for colorblindness in humans.

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How Dogs Are Helping Researchers Cure Color Blindness | The Bark - The Bark (blog)