Archive for the ‘Gene Therapy Research’ Category

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Dr. Lewis A. Chodosh is a physician-scientist who received a BS in Molecular Biophysics and Biochemistry from Yale University, and MD from Harvard Medical School, and a PhD. in Biochemistry from M.I.T. in the laboratory of Dr. Phillip Sharp.He performed his clinical training in Internal Medicine and Endocrinology at the Massachusetts General Hospital, after which he was a postdoctoral research fellow with Dr. Philip Leder at Harvard Medical School.Dr. Chodosh joined the faculty of the University of Pennsylvania in 1994, where he is currently a Professor in the Departments of Cancer Biology, Cell & Developmental Biology, and Medicine. He serves as Chairman of the Department of Cancer Biology, Associate Director for Basic Science of the Abramson Cancer Center, and Director of Cancer Genetics for the Abramson Family Cancer Research Institute at the University of Pennsylvania. Additionally, heis on the scientific advisory board for the Harvard Nurses' Health Studies I and II.

Dr. Chodosh's research focuses on genetic, genomic and molecular approaches to understanding breast cancer susceptibility and pathogenesis.

More here:
Breast Cancer Research | Home page

Track-1 Cell Therapy:

Cell therapyas performed by alternativemedicinepractitioners is very different from the controlled research done by conventionalstem cellmedical researchers. Alternative practitioners refer to their form of cell therapy by several other different names includingxenotransplanttherapy,glandular therapy, and fresh cell therapy. Proponents ofcell therapyclaim that it has been used successfully to rebuild damaged cartilage in joints, repair spinal cord injuries,strengthen a weakenedimmune system, treat autoimmune diseases such as AIDS, and help patients withneurological disorderssuch as Alzheimers disease,Parkinson's diseaseand epilepsy.

Related Conferences:

6th International Conference onTissue Engineering & Regenerative Medicine, Baltimore, USA, Aug 20-22, 2017,8th World Congress and Expo onCell & Stem Cell Research,Orlando, USA, March 20-22, 2017,15thWorld Congress on Biotechnology and Biotech Industries Meet,Rome, Italy,March 20-21,2017 ,2nd International Conference onGenetic Counselling and Genomic Medicine ,Beijing, China,July 10-12, 2017, International Conference onClinical and Molecular Genetics, Las Vegas, USA, April 24-26, 2017.

Track-2 Gene therapy:

Gene therapyand cell therapy are overlapping fields of biomedical research with the goals of repairing the direct cause of genetic diseases in the DNA orcellularpopulation, respectively. The development of suitablegene therapytreatments for manygenetic diseasesand some acquired diseases has encountered many challenges and uncovered new insights into gene interactions and regulation. Further development often involves uncovering basic scientific knowledge of the affected tissues, cells, and genes, as well as redesigning vectors, formulations, and regulatory cassettes for the genes.Cell therapyis expanding its repertoire of cell types for administration.Cell therapytreatment strategies include isolation and transfer of specific stem cell populations, administration of effector cells, and induction of mature cells to becomepluripotent cells, and reprogramming of mature cells.

Related Conferences:

2nd International Conference onMolecular Biology,London, UK,June 22-24, 2017,3rd World Bio Summit & Expo, Abu Dhabi, UAE, June 19-21, 2017,5th International Conference onIntegrative Biology, London, UK, June 19-21,2017,2nd World Congress on Human Genetics, Chicago, USA, July 24-26, 2017,9th International Conference onGenomics and Pharmacogenomics, Chicago, USA, July 13-14, 2017.

Track-3 Cell and gene therapy products:

Articles containing or consisting ofhuman cellsor tissues that are intended for implantation,transplantation, infusion, or transfer to a human recipient.Gene therapiesare novel and complex products that can offer unique challenges in product development. Hence, ongoing communication between the FDA and stakeholders is essential to meet these challenges.Gene therapy productsare being developed around the world, the FDA is engaged in a number of international harmonization activities in this area.

Examples:Musculoskeletal tissue, skin, ocular tissue, human heart valves;vascular graft, dura mater, reproductive tissue/cells, Stem/progenitor cells,somatic cells, Cells transduced withgene therapyvectors , Combination products (e.g., cells or tissue + device)

Related Conferences:

Track-4 Cellular therapy:

Cellular therapy, also calledlive cell therapy, cellular suspensions, glandular therapy, fresh cell therapy, sick cell therapy,embryonic cell therapy, andorgan therapy- refers to various procedures in which processed tissue from animal embryos, foetuses or organs, is injected or taken orally. Products are obtained from specific organs or tissues said to correspond with the unhealthy organs or tissues of the recipient. Proponents claim that the recipient's body automatically transports the injected cells to thetarget organs, where they supposedly strengthen them and regenerate their structure. The organs and glands used in cell treatment include brain, pituitary,thyroid, adrenals, thymus, liver,kidney, pancreas, spleen, heart,ovary, testis, and parotid. Several different types of cell or cell extract can be given simultaneously - some practitioners routinely give up to 20 or more at once.

Related Conferences:

3rd International Conference onSynthetic Biology, Munich, Germany, July 20-21, 2017, 5th International Conference and Exhibition onCell and Gene Therapy,Madrid, Spain,Mar 2-3,2017,International Conference onCell Signalling and Cancer Therapy, Aug 20-22, 2017, Paris, France,7th Annual Conference on Stem Cell and Regenerative Medicine, Aug 04-05, 2016, Paris, France,3rd International Conference & Exhibition onTissue Preservation and Bio banking, June 29-30, 2017, Baltimore, USA.

Track-5 Cancer gene therapy:

Cancer therapiesare drugs or other substances that block the growth and spread ofcancerby interfering with specific molecules ("molecular targets") that are involved in the growth, progression, and spread ofcancer. Many cancer therapies have been approved by the Food and Drug Administration (FDA) to treat specific types of cancer. The development of targetedtherapiesrequires the identification of good targets that is, targets that play a key role in cancer cell growth and survival. One approach to identify potential targets is to compare the amounts of individualproteinsin cancer cells with those in normal cells.Proteinsthat are present in cancer cells but not normal cells or that are more abundant incancercells would be potential targets, especially if they are known to be involved incell growthor survival.

Related Conferences:

2nd Biotechnology World Convention,London, UK,May 25-27, 2017, ,International Conference on Animal and Human Cell Culture, Jackson Ville, USA, Sep 25-27, 2017,9th International Conference onCancer Genomics, Chicago, USA, May 29-31, 2017, 6th International Conference onTissue Engineering & Regenerative Medicine, Baltimore, USA, Aug 20-22, 2017,8th World Congress and Expo onCell & Stem Cell Research, Orlando, USA, March 20-22, 2017.

Track-6 Nano therapy:

Nano Therapymay be defined as the monitoring, repair, construction and control of human biological systems at themolecular level, using engineerednanodevicesand nanostructures. Basic nanostructured materials, engineeredenzymes, and the many products of biotechnology will be enormously useful in near-term medical applications. However, the full promise ofnanomedicineis unlikely to arrive until after the development of precisely controlled or programmable medical Nano machines andnanorobots.

Related Conferences:

15thWorld Congress on Biotechnology and Biotech Industries Meet March,Rome, Italy,20-21, 2017,2nd International Conference onGenetic Counselling and Genomic Medicine ,Beijing, China,July 10-12, 2017, , International Conference onClinical and Molecular Genetics, Las Vegas, USA, April 24-26, 2017, 15th Euro Biotechnology Congress, Valencia, Spain, June 05-07, 2017,International Conference onIntegrative Medicine & Nutrition, Dubai, UAE, May11-13, 2017.

Track-7 Skin cell therapy:

Stem cellshave newly become a huge catchphrase in theskincarebiosphere. Skincare specialists are not usingembryonic stem cells; it is impossible to integrate live materials into a skincare product. Instead, scientists are creating products with specialized peptides andenzymesor plantstem cellswhich, when applied topically on the surface, help to protect the human skinstem cellsfrom damage and deterioration or stimulate the skins own stem cells. Currently, the technique is mainly used to save the lives of patients who have third degree burns over very large areas of their bodies.

Related Conferences:

5th International Conference and Exhibition onCell and Gene Therapy,Madrid,Spain,Mar 2-3, 2017, ,International Conference onCell Signalling and Cancer Therapy,Paris, France,Aug 20-22, 2017,2nd Biotechnology World Convention,London, UK,May 25-27, 2017,International Conference on Animal and Human Cell Culture,Jackson Ville, USA, Sep 25-27, 2017,9th International Conference onCancer Genomics, Chicago, USA, May 29-31, 2017.

Track-8 HIV gene therapy:

Highly activeantiretroviral therapydramatically improves survival inHIV-infected patients. However, persistence of HIV in reservoirs has necessitated lifelong treatment that can be complicated bycumulative toxicities, incomplete immune restoration, and the emergence of drug-resistant escapemutants. Cell and gene therapies offer the promise of preventing progressiveHIV infectionby interfering with HIV replication in the absence of chronicantiviral therapy.

Related Conferences:

3rd International Conference onSynthetic Biology, Munich, Germany, July 20-21, 2017, International Conference onIntegrative Medicine & Nutrition, Dubai, UAE, May 11-13, 2017, International Conference on Animal and Human Cell Culture, Jackson Ville, USA, Sep 25-27, 2017, International Conference onCell Signalling and Cancer Therapy, Aug 20-22, 2017,Paris, France.

Track-9 Diabetes for gene therapy:

Cell therapyapproaches for this disease are focused on developing the most efficient methods for the isolation ofpancreasbeta cells or appropriatestem cells, appropriate location forcell transplant, and improvement of their survival upon infusion. Alternatively, gene andcell therapyscientists are developing methods to reprogram some of the other cells of the pancreas to secreteinsulin. Currently ongoingclinical trialsusing these gene andcell therapystrategies hold promise for improved treatments of type I diabetes in the future. The firstgene therapyapproach to diabetes was put forward shortly after the cloning of theinsulingene. It was proposed that non-insulin producing cells could be made into insulin-producingcells using a suitable promoter and insulin gene construct, and that these substitute cells could restore insulin production in type 1 and some type 2 diabetics.

Related Conferences:

15thWorld Congress on Biotechnology and Biotech Industries Meet,Rome, Italy,March 20-21, 2017, 6th International Conference onTissue Engineering & Regenerative Medicine, Baltimore, USA, Aug 20-22, 2017,8th World Congress and Expo onCell & Stem Cell Research, Orlando, USA, March 20-22, 2017, 14th Asia-Pacific Biotech Congress,Beijing, China,April 10-12, 2017,5th International Conference onIntegrative Biology, London, UK, June 19-21, 2017.

Track-10 Viral gene therapy:

Converting avirusinto a vector Theviral life cyclecan be divided into two temporally distinct phases: infection and replication. Forgene therapyto be successful, an appropriate amount of a therapeutic gene must be delivered into the target tissue without substantial toxicity. Eachviral vectorsystem is characterized by an inherent set of properties that affect its suitability for specific gene therapy applications. For some disorders, long-term expression from a relatively small proportion of cells would be sufficient (for example, genetic disorders), whereas otherpathologiesmight require high, but transient,gene expression. For example, gene therapies designed to interfere with a viral infectious process or inhibit the growth ofcancer cellsby reconstitution of inactivated tumour suppressor genes may require gene transfer into a large fraction of theabnormal cells.

Related Conferences:

Track-11 Stem cell therapies:

Stem cells have tremendous promise to help us understand and treat a range of diseases, injuries and other health-related conditions. Their potential is evident in the use ofblood stem cellsto treat diseases of the blood, a therapy that has saved the lives of thousands of children withleukaemia; and can be seen in the use ofstem cellsfor tissue grafts to treat diseases or injury to the bone, skin and surface of the eye. Some bone, skin andcorneal(eye) injuries and diseases can be treated bygraftingor implanting tissues, and the healing process relies on stem cells within thisimplanted tissue.

Related Conferences:

2nd World Congress on Human Genetics, Chicago, USA, July 24-26, 2017, 2nd International Conference onGenetic Counselling and Genomic Medicine ,Beijing, China,July 10-12, 2017, , International Conference onClinical and Molecular Genetics, Las Vegas, USA, April 24-26, 2017,2nd International Conference onMolecular Biology,London, UK,June 22-24, 2017, 15th Biotechnology Congress, Baltimore, USA, June 22-23, 2017.

Track-12 Stem cell preservation:

The ability to preserve the cells is critical to theirclinicalapplication. It improves patient access to therapies by increasing the genetic diversity of cells available. In addition, the ability to preserve cells improves the "manufacturability" of acell therapyproduct by permitting the cells to be stored until the patient is ready for administration of the therapy, permitting inventory control of products, and improving management of staffing atcell therapyfacilities. Finally, the ability to preservecell therapiesimproves the safety of cell therapy products by extending the shelf life of a product and permitting completion of safety and quality control testing before release of the product for use. preservation permits coordination between the manufacture of the therapy and patient care regimes.

Related Conferences:

7th Annual Conference on Stem Cell and Regenerative Medicine,Paris,France,Aug 04-05,2016,2nd Biotechnology World Convention,LONDON, UK,May 25-27, 2017, ,International Conference on Animal and Human Cell Culture, Jackson Ville, USA, Sep 25-27, 2017,9th International Conference onCancer Genomics, Chicago, USA, May 29-31, 2017, 3rd International Conference onSynthetic Biology, Munich, Germany, July 20-21, 2017.

Track-13 Stem cell products:

The globalstemcell,Stem cell productsmarket will grow from about $5.6 billion in 2013 to nearly $10.6 billion in 2018, registering a compound annual growth rate (CAGR) of 13.6% from 2013 through 2018.This trackdiscusses the implications ofstemcellresearchand commercial trends in the context of the current size and growth of thepharmaceutical market, both in global terms and analysed by the most important national markets.

Related Conferences:

6th International Conference onTissue Engineering & Regenerative Medicine, Baltimore, USA, Aug 20-22, 2017,8th World Congress and Expo onCell & Stem Cell Research, Orlando, USA, March 20-22, 2017,15thWorld Congress on Biotechnology and Biotech Industries Meet,Rome, Italy,March 20-21, 2017 ,2nd International Conference onGenetic Counselling and Genomic Medicine , Beijing, China,July 10-12, 2017, ,International Conference onClinical and Molecular Genetics, las vegas, USA, April 24-26, 2017.

Track-14 Genetically inherited diseases:

Related Conferences:

15th Biotechnology Congress, Baltimore, USA, June 22-23, 2017,3rd International Conference onSynthetic Biology, Munich, Germany, July 20-21, 2017,5th International Conference and Exhibition onCell and Gene Therapy,Madrid, Spain,Mar 2-3, 2017, ,International Conference onCell Signalling and Cancer Therapy,paris, France,Aug 20-22, 2017,, International Conference on Animal and Human Cell Culture, Jackson Ville, USA, Sep 25-27, 2017.

Track-15 Plant stem cells:

Related Conferences:

9th International Conference onGenomics and Pharmacogenomics, Chicago, USA, July 13-14, 2017,7th International Conference onPlant Genomics, Bangkok, Thailand, July 03-05, 2017,15th Euro Biotechnology Congress, Valencia, Spain, June 05-07, 2017,5th International Conference and Exhibition onCell and Gene Therapy,Madrid, Spain,Mar 2-3,2017,3rd International Conference & Exhibition onTissue Preservation and Bio banking,Baltimore, USA,June 29-30, 2017.

Track-16 Plant stem cell rejuvenation:

Asplantscannot escape from danger by running or taking flight, they need a special mechanism to withstandenvironmental stress. What empowers them to withstand harsh attacks and preserve life is the stem cell. According to Wikipedia, plantstem cellsnever undergo theagingprocess but constantly create new specialized and unspecialized cells, and they have the potential to grow into any organ, tissue, or cell in the body. The everlasting life is due to the hormones auxin andgibberellin. British scientists found that plant stem cells were much more sensitive toDNAdamage than other cells. And once they sense damage, they trigger death of these cells.

Rejuvenate with Plant Stem Cells.

Detoxifyand release toxins on a cellular level. Nourishyour body with vital nutrients. Regenerateyour cells and diminish the effects of aging.

Related Conferences:

International Conference on Animal and Human Cell Culture, Jackson Ville, USA, Sep 25-27, 2017, 14th Asia-Pacific Biotech Congress,Beijing, China,April 10-12, 2017,15th Biotechnology Congress, Baltimore, USA, June 22-23, 2017,3rd International Conference onSynthetic Biology, Munich, Germany, July 20-21, 2017,5th International Conference and Exhibition onCell and Gene Therapy,Madrid, Spain,Mar 2-3, 2017.

Track-17 Clinical trials in cell and gene therapy:

Aclinical trialis a research study that seeks to determine if a treatment is safe and effective. Advancing new cell andgene therapies(CGTs) from the laboratory into early-phaseclinical trialshas proven to be a complex task even for experienced investigators. Due to the wide variety ofCGTproducts and their potential applications, a case-by-case assessment is warranted for the design of each clinical trial.

Objectives:Determine thepharmacokineticsof this regimen by the persistence of modified T cells in the blood of these patients, Evaluate theimmunogenicityof murine sequences in chimeric anti-CEA Ig TCR, Assess immunologic parameters which correlate with the efficacy of this regimen in these patients, Evaluate, in a preliminary manner, the efficacy of this regimen in patients with CEA bearingtumours.

Related Conferences:

2nd Biotechnology World Convention,London, UK,May 25-27, 2017, ,International Conference on Animal and Human Cell Culture, Jackson Ville, USA, Sep 25-27, 2017,9th International Conference onCancer Genomics, Chicago, USA, May 29-31, 2017, 8th World Congress and Expo onCell & Stem Cell Research, Orlando, USA, March 20-22, 2017,15thWorld Congress on Biotechnology and Biotech Industries Meet,Rome, Italy,March 20-21, 2017.

Track-18 Molecular epigenetics:

Epigeneticsis the study of heritable changes in thephenotypeof a cell or organism that are not caused by its genotype. The molecular basis of anepigeneticprofile arises from covalent modifications of protein andDNAcomponents ofchromatin. The epigenetic profile of a cell often dictates cell fate, as well as mammalian development,agingand disease. Epigenetics has evolved to become the science that explains how the differences in the patterns ofgene expressionin diverse cells or tissues are executed and inherited.

Related Confderences:

5th International Conference onIntegrative Biology, London, UK, June 19-21, 2017,2nd World Congress on Human Genetics, Chicago, USA, July 24-26, 2017,9th International Conference onGenomics and Pharmacogenomics, Chicago, USA, July 13-14, 2017, International Conference onIntegrative Medicine & Nutrition, Dubai, UAE, May11-13, 2017,14th Asia-Pacific Biotech Congress,Beijing, China,April 10-12, 2017.

Track-19 Bioengineering therapeutics:

The goals ofbioengineeringstrategies for targetedcancertherapies are (1) to deliver a high dose of an anticancer drug directly to a cancer tumour, (2) to enhance drug uptake by malignant cells, and (3) to minimize drug uptake by non-malignant cells. In ESRD micro electro mechanical systems andnanotechnologyto create components such as robust silicon Nano pore filters that mimic natural kidney structure for high-efficiency toxin clearance. It also usestissue engineeringto build a miniature bioreactor in which immune-isolated human-derived renal cells perform key functions, such as reabsorption of water and salts.In drug delivery for a leading cause ofblindness, photo-etching fabrication techniques from themicrochipindustry to create thin-film and planar micro devices (dimensions in millionths of meters) with protectivemedicationreservoirs andnanopores(measured in billionths of meters) for insertion in the back of the eye to deliver sustained doses of drug across protective retinalepithelial tissuesover the course of several months.

Related Conferences:

6th International Conference onTissue Engineering & Regenerative Medicine, Baltimore, USA, Aug 20-22, 2017,8th World Congress and Expo onCell & Stem Cell Research, Orlando, USA, March 20-22, 2017,15thWorld Congress on Biotechnology and Biotech Industries Meet,Rome, Italy,March 20-21, 2017 ,2nd International Conference onGenetic Counselling and Genomic Medicine ,Beijing, China,July 10-12, 2017, ,International Conference onClinical and Molecular Genetics, Las Vegas, USA, April 24-26, 2017.

Track-20 Advanced gene therapy:

Advanced therapiesare different fromconventional medicines, which are made from chemicals or proteins.Gene-therapymedicines:these contain genes that lead to atherapeuticeffect. They work by inserting 'recombinant' genes into cells, usually to treat a variety of diseases, including genetic disorders, cancer or long-term diseases.Somatic-cell therapymedicines:these contain cells or tissues that have been manipulated to change their biological characteristics.Advanced Cell &Gene Therapyprovides guidanceinprocess development, GMP/GTP manufacturing,regulatory affairs, due diligence and strategy, specializing in cell therapy,gene therapy, and tissue-engineeredregenerative medicineproducts.

Related Conferences:

2nd Biotechnology World Convention,London, UK,May 25-27, 2017, ,15th Biotechnology Congress, Baltimore, USA, June 22-23, 2017,3rd International Conference onSynthetic Biology, Munich, Germany, July 20-21, 2017,5th International Conference and Exhibition onCell and Gene Therapy,Madrid, Spain,Mar 2-3, 2017, ,International Conference onCell Signalling and Cancer Therapy,paris, France,Aug 20-22, 2017, International Conference on Animal and Human Cell Culture, Jackson Ville, USA, Sep 25-27, 2017.

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What Is Gene Therapy?

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

Gene Delivery: Tools of the Trade

Explore the methods for delivering genes into cells.

Space Doctor

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

Challenges In Gene Therapy

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

Approaches To Gene Therapy

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

Gene Therapy Successes

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

Gene Therapy Case Study: Cystic Fibrosis

APA format:

Genetic Science Learning Center. (2012, December 1) Gene Therapy. Retrieved August 05, 2016, from http://learn.genetics.utah.edu/content/genetherapy/

CSE format:

Gene Therapy [Internet]. Salt Lake City (UT): Genetic Science Learning Center; 2012 [cited 2016 Aug 5] Available from http://learn.genetics.utah.edu/content/genetherapy/

Chicago format:

Genetic Science Learning Center. "Gene Therapy." Learn.Genetics. December 1, 2012. Accessed August 5, 2016. http://learn.genetics.utah.edu/content/genetherapy/.

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Gene Therapy - Learn Genetics

For 26 years, doctors could not piece together the medical puzzle of Stewart Altman's symptoms -- as a child growing up on Long Island, he was uncoordinated and slurred his speech. Later, as a volunteer fireman, he kept falling down and had trouble climbing the ladders.

It seemed unrelated at the time, but his older sister, who had a history of psychological symptoms, was hospitalized in a mental institution. Her psychiatrist suspected a physical disorder and consulted a geneticist who eventually connected the dots.

In 1978, Altman and his sister Roslyn Vaccaro were given a stunning diagnosis: Tay-Sachs -- an inherited neurological disease that typically affects babies, killing them between the ages of 3 and 5. Only several hundred cases exist in the United States.

Altman, now 58, has a non-fatal, adult form of the disease, late onset Tay-Sachs (LOTS), and depends on his wife and a service dog to perform most daily tasks.

"I am devastated," Altman said of the disease that has robbed him of much of his speech and muscle strength, confining him to a wheelchair. "But the alternative is much worse."

His sister died in 2000 after battling LOTS-related bipolar disorder and schizophrenia -- which occurs in 50 to 60 percent of all adult cases -- and Altman and his wife raised her two sons.

Now scientists are hopeful that gene therapy may help late-onset patients like Altman and look forward to human trials.

Tay-Sachs is caused by gene mutation results in the absence or insufficient levels of the enzyme, hexosamindase A or Hex A. Without it, a fatty substance or lipids accumulates in the cells, mostly in the brain. It comes in three forms: infantile, juvenile or adult onset.

Doctors say there can be great variations in the presentation of Tay-Sachs, even in the same family with the same mutations. Babies born with Tay-Sachs appear normal at first, but by 3 or 4 years old, their nerve cells deteriorate and they eventually die. Those with LOTS can live a long life, but, like Altman, are progressively disabled.

The story of Tay-Sachs is a miraculous one. It was first identified in the late 1800s by British ophthalmologist Warren Tay and New York neurologist Bernard Sachs, who noticed the disease was prevalent in Jews of Eastern European origin.

In the 1970s and 1980s, when genetic testing became available, synagogues launched public education campaigns encouraging prospective parents to be tested, and the disease was virtually eliminated in those of Jewish ancestry.

Now, mostly non-Jews, though their risk is not as great, are among the 100 American children who have the disease, according to the National Tay-Sachs and Allied Diseases Association (NTSAD), which leads the fight for a cure.

Altman's speech is difficult to understand, so his wife Lorrie said her husband of 37 years wanted the public to know, "it's not just an infant's disease."

"Tay-Sachs is also in the general population and people don't know," she said. "He thinks we need to get the word out. One in 250 Americans carries the gene."

French Canadians, Louisiana Cajuns and even those of English-Irish ancestry have a greater chance of carrying the recessive gene that causes the disease.

Tay-Sachs is an autosomal recessive disorder, which means each parent must carry the gene. Their children have a 25 percent chance of developing Tay-Sachs, 50 percent chance of being a carrier and a 25 percent chance of being free of that recessive gene.

Altman was born in 1952, before genetic testing was available. Both his parents were carriers of the recessive gene that causes Tay-Sachs and both he and sister were stricken with the mildest form of the disease. Two of their brothers were unaffected, although one is a carrier.

The Massapequa, N.Y., couple have two healthy sons, who are carriers, but whose wives are not, and four healthy grandchildren.

For years, Altman was able to get around with a walker until he had to drop out of a clinical trial for a new drug because of debilitating side effects. After that, he said he lost 40 pounds and so much muscle that he could no longer stand on his own.

"Between the two of us we handle it and we lead kind of a normal life," said Lorrie. "But we have no idea what the future will bring."

Altman works at Nassau University Medical Center in the security monitoring department. He raises funds for about 11 different non-profit organizations, including NTSAD, and has given presentations to the Boy Scouts and senior citizens.

Much of the public work has now ended, as his speech has become more incomprehensible because the degeneration of the nerves that control his respiratory muscles.

"Stewart has a good way of just living in the moment," said his wife, who met Altman in college. "But the worst part for him is his speech. He is such a social, outgoing person."

He has faced discrimination along the way, especially after leaving a Manhattan engineering job because he couldn't climb the subway stairs.

"He has such a hard time getting a job -- it was devastating," said Lorrie Altman. "On paper, he looked so good, but his speech was terrible. He has a college degree and isn't stupid, but all people see is the wheelchair."

Doctors say that many with the milder adult form of Tay-Sachs can lead full lives, despite their disability. And science is getting closer to finding treatments for this devastating disease.

Dr. Edwin Kolodny, former department chair and now professor of neurology at New York University School of Medicine, has been a leader in the field for 30 years. He first helped identify the role of the enzyme Hex-A and later tested more than 30,000 young adults in the 1970s and 1980s.

Today, he and others are involved in the promising gene therapy studies involving first mice, then cats and now sheep. Injecting genes into the brains of Jacob lambs has doubled their life span.

Clinical trials on humans are set to begin as soon as researchers can raise another $700,000 -- in addition to a grant from the National Institutes of Health -- to manufacture the vectors required to insert the genes into the body.

"It seems like every parent in the world would like to be part of the trial," said Kolodny. "And there are reasons to think there will be success here, especially for children who have a slightly later onset and not the classic form Tay-Sachs."

In the past, infantile Tay-Sachs has seen most of the medical attention. "These children have zero quality of life," he said.

Those with mild mutations, like Altman, who have 5 to 10 percent of Hex A enzyme activity, "sometimes lead full lives," according to Kolodny. "Intellectually, most of their cognitive function is retained. We have patients who are lawyers and accountants."

Pre-conception testing is still the gold standard for fighting the disease. "If your parents don't have the same recessive genes, you are home free," he said.

Those identified as at risk for having a child with Tay-Sachs can decide to adopt or conceive through in vitro fertilization, where geneticists can test the embryos before implantation to ensure the child will be disease-free.

Doctors can also do prenatal genetic testing and if the fetus is affected, the decision is up to the parents whether or not they want to terminate the pregnancy. "Three out of four times, they are reassured they have a normal child," said Kolodny.

Doctors say such testing -- at a cost of around $100 -- should be done routinely for 18 autosomal recessive disorders, including the gene for cystic fibrosis, which occurs in one in 20 caucasians, said Kolodny. Even with advances in Tay-Sachs testing in the Jewish community, public education must continue.

"The problem is each generation forgets what happened in the prior generation -- the grandmothers die out, " said Kolodny. "We need to educate health care professionals. Each new group of students graduating from medical school isn't prepared to ask the right questions."

Susan Kahn, NTSAD's executive director, who is involved in fundraising for research, agrees that along with a fight for a cure, genetic testing is critical.

"When there is a genetic disease, it's not just about that person, there is a whole implication for the rest of the family and how they deal with it," she said.

Stewart Altman sits on the association's board of directors and is a tireless crusader for a cure.

"He's got some disabilities that make it difficult for him to do certain things, but of all the board members asking for money to support, he is probably the boldest in our group," said Kahn. "He does have a lot of limitations, but he is still very energetic and wants to do something important. Not everyone responds with the same attitude."

His wife Lorrie backed that up with a laugh. "He is persistent," she said. "He carries these little envelopes around and will ask anyone he meets for a donation. It's almost embarrassing. He's not afraid to ask."

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Gene Therapy in Sheep May Bring Hope to Adults With Tay ...

Clin Microbiol Rev. 2008 Oct; 21(4): 583593.

Department of Molecular Genetics and Microbiology, College of Medicine,1 University of Florida Genetics Institute, University of Florida, Gainesville, Florida2

Summary: The unique life cycle of adeno-associated virus (AAV) and its ability to infect both nondividing and dividing cells with persistent expression have made it an attractive vector. An additional attractive feature of the wild-type virus is the lack of apparent pathogenicity. Gene transfer studies using AAV have shown significant progress at the level of animal models; clinical trials have been noteworthy with respect to the safety of AAV vectors. No proven efficacy has been observed, although in some instances, there have been promising observations. In this review, topics in AAV biology are supplemented with a section on AAV clinical trials with emphasis on the need for a deeper understanding of AAV biology and the development of efficient AAV vectors. In addition, several novel approaches and recent findings that promise to expand AAV's utility are discussed, especially in the context of combining gene therapy ex vivo with new advances in stem or progenitor cell biology.

Adeno-associated virus (AAV) vectors are currently among the most frequently used viral vectors for gene therapy. At recent meetings of the American Society for Gene Therapy, nearly half of the presentations involved the use of AAV. This represents a significant turnaround. Historically, AAV has not been of great medical interest, because it has not been identified as a pathogen; thus, the lack of widespread knowledge of the virus initially inhibited its broad use as a vector. Twelve human serotypes of AAV (AAV serotype 1 [AAV-1] to AAV-12) and more than 100 serotypes from nonhuman primates have been discovered to date. The lack of pathogenicity of the virus, the persistence of the virus, and the many available serotypes have increased AAV's potential as a delivery vehicle for gene therapy applications. This review will focus on the biology of AAV and its use as a vector for gene therapy.

AAV is a small (25-nm), nonenveloped virus that packages a linear single-stranded DNA genome. It belongs to the family Parvoviridae and is placed in the genus Dependovirus, because productive infection by AAV occurs only in the presence of a helper virus, either adenovirus or herpesvirus. In the absence of helper virus, AAV (serotype 2) can set up latency by integrating into chromosome 19q13.4, establishing itself as the only mammalian DNA virus known to be capable of site-specific integration.

The AAV-2 genome is a linear, single-stranded DNA of 4.7 kb (Fig. ) (60). Both sense and antisense strands of AAV DNA are packaged into AAV capsids with equal frequency. The genome is structurally characterized by 145-bp inverted terminal repeats (ITRs) that flank two open reading frames (ORFs) (Fig. ).

Map of the wild-type AAV-2 genome. (A) Rep and Cap genes flanked by ITRs. The different Rep and Cap transcripts are produced from their respective promoters (P5, P19, and P40). The star indicates the alternative ACG codon used to produce VP3. (B) Secondary ...

The first 125 nucleotides of the ITR constitute a palindrome, which folds upon itself to maximize base pairing and forms a T-shaped hairpin structure. The other 20 bases, called the D sequence, remain unpaired. The ITRs are important cis-active sequences in the biology of AAV. A key role of the ITRs is in AAV DNA replication. In the current model of AAV replication, the ITR is the origin of replication and serves as a primer for second-strand synthesis by DNA polymerase. The double-stranded DNA formed during the synthesis, called replicating-form monomer, is used for a second round of self-priming replication and forms a replicating-form dimer. These double-stranded DNA intermediates (replicating-form monomer and replicating-form dimer) are processed via a strand displacement mechanism, resulting in single-stranded DNA used for packaging and double-stranded DNA used for transcription. Critical to the replication process are the Rep binding elements (RBEs) (RBE and RBE) and a terminal resolution site (TRS), which is located within the ITR (Fig. ). These features are used by the viral regulatory protein Rep during AAV replication to process the double-stranded intermediates. In addition to their role in AAV replication, the ITR is also essential for AAV genome packaging, transcription, negative regulation under nonpermissive conditions, and site-specific integration.

The left ORF contains the Rep gene, which produces four Rep proteins, Rep78, Rep68, Rep52, and Rep40. The larger Rep proteins (Rep78 and Rep68) are produced from transcripts using the P5 promoter, whereas the smaller Rep proteins (Rep52 and Rep40) are produced from transcripts using the P19 promoter. Rep78 and Rep68 are produced from unspliced and spliced transcripts, respectively, and are important regulatory proteins that act in trans in all phases of the AAV life cycle. Specifically, they positively and negatively regulate AAV gene expression in the presence or absence of helper virus, respectively, and are required for DNA replication (48). The smaller Rep proteins, Rep52 and Rep40, produced from unspliced and spliced transcripts, respectively, are involved in the accumulation of single-stranded viral DNA used for packaging within AAV capsids. All four Rep proteins possess helicase and ATPase activity. In addition, the larger Rep proteins possess strand- and site-specific endonuclease activity (nicking at the TRS) and site-specific DNA binding activity (binding at the RBE).

The right ORF contains the Cap gene, which produces three viral capsid proteins (VP1, VP2, and VP3) using the P40 promoter. Alternative splicing of the P40 transcript is used to produce the three viral proteins from two transcripts. The unspliced transcript produces VP1 (87 kDa), the biggest of the capsid proteins. The spliced transcript produces VP2 (72 kDa) and VP3 (62 kDa). VP2 is produced using a nonconventional ACG start codon, whereas VP3 is produced using a downstream conventional AUG codon. The AAV-2 capsid comprises 60 viral capsid proteins arranged into an icosahedral structure with symmetry equivalent to a triangulation number of 1. The capsid proteins (VP1, VP2, and VP3) are present in a 1:1:10 molar ratio.

There are two stages to the AAV life cycle (Fig. ) after successful infection, a lytic stage and a lysogenic stage. In the presence of helper virus (adenovirus or herpesvirus), the lytic stage ensues. During this period, AAV undergoes productive infection characterized by genome replication, viral gene expression, and virion production. The adenoviral genes that provide helper functions regarding AAV gene expression have been identified and include E1a, E1b, E2a, E4, and VA RNA. Herpesvirus aids in AAV gene expression by providing viral DNA polymerase and helicase as well as the early functions necessary for HSV transcription. Although adenovirus and herpesvirus provide different sets of genes for helper function, they both regulate cellular gene expression, providing a permissive intracellular milieu for AAV productive infection.

AAV life cycle. AAV undergoes productive infection in the presence of adenovirus coinfection. This is characterized by genome replication, viral gene expression, and virion production. In the absence of adenovirus, AAV can establish latency by integrating ...

In the absence of adenovirus or herpesvirus, there is limited AAV replication, viral gene expression is repressed, and the AAV genome can establish latency by integrating into a 4-kb region on chromosome 19 (q13.4), termed AAVS1 (36, 37). The AAVS1 locus is near several muscle-specific genes, TNNT1 and TNNI3 (16). The AAVS1 region itself is an upstream part of a recently described gene, MBS85. The exact function of this gene is not clear, but its product has been shown to be involved in actin organization (64). Whether AAV integration into this site is suitable for human gene therapy applications remains to be evaluated. Tissue culture experiments suggest that the AAVS1 locus is a safe integration site.

One of the features of AAV is its ability to specifically integrate to establish latent infection. Current AAV vectors do not have this ability, and the development of such a vector would ensure long-term transgene expression in tissues without problems associated with insertional mutagenesis.

Some of the viral and cellular requirements for targeted integration have been elucidated. The AAV components that are required have been identified. These include the ITRs (in cis), Rep78 or Rep68 (in trans), and a 138-bp sequence termed the integration efficiency element (IEE), located within the P5 promoter in cis (49). It is unclear if the entire 138-bp IEE in P5 is required, since a recent study showed that a 16-bp RBE in P5 is sufficient (18). Latent infection with wild-type AAV-2 appears to be nonpathogenic in tissue culture, when Rep is expressed under its own promoter. Such expression is regulated by negative feedback. Excess Rep expression has been shown to arrest cell division (75) and induce cellular apoptosis (58).

A 33-bp minimum AAVS1 sequence, which contains an RBE-like and a TRS-like sequence separated by 8 nucleotides, is necessary and sufficient to target AAV integration (26). The intervening sequence may be varied, but a central 5 CTC is required. The actual integration site is somewhat downstream from the target sequence and can be variable. Many RBEs have been identified in the human genome, with AAVS1 being the only site that has an RBE and a TRS in close proximity to one other. Interestingly, the AAV genome and AAVS1 can be tethered to each other via Rep68 in vitro (68). These observations provide a molecular explanation for why AAVS1 is targeted, even though the exact mechanism remains unknown.

The process of site-specific integration is not completely specific even under ideal conditions of Rep78 and Rep68 expression, with approximately 40 to 70% of integrants occurring in AAVS1. Moreover, the mechanism is imprecise, as judged by there not being reproducible breakpoints for vector-AAVS1 junctions; however, clusters of integrants appear within a 2-kb fragment of AAVS1. While the cis- and trans-acting viral factors required for site-specific integration have been identified, much less is known about cellular factors that are required or may be involved. Only recently has a study provided evidence that a cellular protein, human immunodeficiency virus transacting response element-RNA loop binding protein 185 (TRP-185), can promote AAV integration into AAVS1 further downstream from the RBE via interactions with both Rep and AAVS1 (73). Moreover, site-specific integration has been demonstrated in mice and rats transgenic for AAVS1, suggesting that the AAVS1 open-chromatin structure is maintained in vivo and that the cellular factors that mediate site-specific integration are present in nondividing cells (56).

AAV-2 gains entry into target cells by using the cellular receptor heparan sulfate proteoglycan (62). Internalization is enhanced by interactions with one or more of at least six known coreceptors including V5 integrins (63), fibroblast growth factor receptor 1 (53), hepatocyte growth factor receptor (35), v1 integrin (7), and laminin receptor (3). The cellular events that mediate AAV trafficking postentry are not completely characterized. Cells defective for dynamin significantly hindered AAV-2 infection, suggesting that AAV is endocytosed into clathrin-coated vesicles (15). For successful AAV infection, AAV particles need to escape these endocytic vesicles. Infection experiments with bafilomycin A1 (a drug that inhibits the proton pump for endosomes) suggested that the low pH in the endosomes is essential for virus escape and successful infection (9). Moreover, cellular signaling involving the activation of the Rac1 protein and the phosphatidylinositol 3-kinase pathway is necessary for intracellular trafficking of AAV particles using microtubules (57). Interestingly, a conserved phospholipase A2 motif identified in the N terminus of the VP1 protein was reported to be important for successful infection (27). Specifically, the phospholipase A2 motif seemed to be playing a crucial role during AAV trafficking, possibly helping AAV escape the late endosome. Mutational analysis of the AAV capsid structure indicated that the fivefold pore structure may also serve as the site for phospholipase domain presentation during viral infection (10). Moreover, endosomal cysteine proteases, cathepsins B and L, have implied roles in AAV trafficking and capsid disassembly (4). Exactly how AAV enters the nucleus after escaping the endosome is not known and is currently an active area of research. Although AAV is theoretically small enough to enter the nucleus via the nuclear pore complex, an early study suggested that AAV entry may be nuclear pore complex independent (29).

There are several considerations for any viral vector. These include the ability to attach to and enter the target cell, successful transfer to the nucleus, the ability to be expressed in the nucleus for a sustained period of time, and a general lack of toxicity. AAV vectors have been highly successful in fulfilling all of these criteria. Moreover, a variety of modifications have served to enhance their utility. Several considerations have guided the development of current AAV vectors, especially the lack of pathogenicity of the wild-type virus and its persistence.

The small size of the AAV genome and concerns about potential effects of Rep on the expression of cellular genes led to the construction of AAV vectors that do not encode Rep and that lack the cis-active IEE, which is required for frequent site-specific integration. The ITRs are kept because they are the cis signals required for packaging. Thus, current recombinant AAV (rAAV) vectors persist primarily as extrachromosomal elements (1, 59).

rAAV vectors for gene therapy have been based mostly on AAV-2. AAV-2-based rAAV vectors can transduce muscle, liver, brain, retina, and lungs, requiring several weeks for optimal expression. The efficiency of rAAV transduction is dependent on the efficiency at each step of AAV infection: binding, entry, viral trafficking, nuclear entry, uncoating, and second-strand synthesis. Inefficient AAV trafficking (30) and second-strand synthesis (19) have been identified as being rate-limiting factors in AAV gene expression. Interestingly, the binding of cellular protein FKBP52 to the AAV ITR inhibits second-strand synthesis, and this inhibition is dependent on the phosphorylation state of FKBP52 (51, 52, 80). Moreover, epidermal growth factor receptor kinase signaling has been implicated in regulating both AAV trafficking and second-strand synthesis (80).

Several novel AAV vector technologies have been developed to either increase the genome capacity for AAV or enhance gene expression (Fig. ). The idea of trans-splicing AAV vectors has been used to increase AAV vector capacity (74). This system takes advantage of AAV's ability to form head-to-tail concatemers via recombination in the ITRs. In this approach, the transgene cassette is split between two rAAV vectors containing adequately placed splice donor and acceptor sites. Transcription from recombined AAV molecules, followed by the correct splicing of the mRNA transcript, results in a functional gene product. This application becomes useful for using AAV to deliver therapeutic genes up to 9 kb in size. trans splicing has been successfully used for gene expression in the retina (55), the lung (39), and, more recently, muscle (25). trans-Splicing vectors are less efficient than rAAV vectors.

(Left) trans-Splicing approach. The head-to-tail formation of two different AAV vector results in functional product after splicing. (Right) Comparison of scAAV and rAAV vectors.

The design and use of self-complementary AAV (scAAV) vectors to bypass the limiting aspects of second-strand synthesis have been described (44). The rationale underlying the scAAV vector is to shorten the lag time before transgene expression and potentially to increase the biological efficiency of the vector. scAAV vectors can fold upon themselves, immediately forming transcriptionally competent double-stranded DNA. One consequence of the use of scAAV is that the maximal size of the transgene is reduced by 50% (2.4-kb capacity), but up to 3.3 kb of DNA can be encapsidated (71). Rapid transduction has been observed using scAAV in both tissue culture and in vivo experiments.

Many clinically relevant tissues are not susceptible to infection by AAV-2. Greater gene expression was seen in muscle, retina, liver, and heart using AAV serotypes 1, 5, 8, and 9, respectively. The cell surface receptors have been identified for only some of the many AAV serotypes: AAV-3 (heparan sulfate proteoglycan), AAV-4 (O-linked sialic acid), and AAV-5 (platelet-derived growth factor receptor). In addition, a 37-kDa/67-kDa laminin receptor has been identified as being a receptor for AAV serotypes 2, 3, 8, and 9 (3). The attachment receptors for the other serotypes have not yet been identified. All of these serotypes are potential candidates for testing as vectors for gene therapy. To date, most of the testing has involved serotypes 1 to 9, which have considerable differences at the capsid amino acid sequence level, except for AAV-1 and AAV-6 (Table ), and has succeeded in identifying vectors with widely divergent tissue specificities.

Capsid homology among AAV serotypes 1 to 9

The use of the different AAV serotypes in a pseudotyping approach (the genome of one ITR serotype being packaged into a different serotype capsid) has allowed broad tissue tropisms. However, some tissues remain refractory to transduction using available serotypes. This presents a major challenge for AAV-based gene therapy for clinically relevant tissues.

A deeper understanding of the AAV capsid properties has made the rational design of AAV vectors that display selective tissue/organ targeting possible, thus broadening the possible applications for AAV as a gene therapy vector. Two approaches have been used for AAV vector retargeting: (i) direct targeting and (ii) indirect targeting. In direct targeting, vector targeting is mediated by small peptides or ligands that have been directly inserted into the viral capsid sequence. This approach has been used successfully to target endothelial cells (61, 69). Direct targeting requires extensive knowledge of the capsid structure. Important aspects involve the following: peptides or ligands must be positioned at sites that are exposed to the capsid surface, the insertion must not significantly affect capsid structure and assembly, and it is important that the native tropism be ablated to maximize targeting.

In indirect targeting, vector targeting is mediated by an associating molecule that interacts with both the viral surface and the specific cell surface receptor. The use of bispecific antibodies (8) and biotin (6, 50) has been described for AAV vectors. The advantages of this approach are that different adaptors can be coupled to the capsid without significant changes in capsid structure, and the native tropism can be easily ablated. One disadvantage of using adaptors for targeting may involve the decreased stability of the capsid-adaptor complex in vivo. The development of efficient AAV targeting vectors will require a better understanding of all aspects of the AAV infection process: binding and entry, viral processing, and nuclear entry and expression. Significant progress has been made in all these categories, and the development of efficient AAV targeting vectors will expand AAV's use as a vector for many clinical applications.

One of the biggest challenges facing AAV gene delivery is the host immune response. The host defense mechanism at the adaptive level is made up of cell-mediated and humoral immunity. The cell-mediated response functions at the cellular level, eliminating the transduced cells using cytotoxic T cells, whereas the humoral response produces neutralizing antibodies (Nab), preventing the readministration of vector. Almost no innate response is seen in AAV infection (76).

Immune response to AAV is primarily a humoral response (72). Preexisting Nab in patients, because of prior infection, account for the humoral response seen toward AAV. In a study by Chirmule et al. (13), antibodies to AAV were seen in 96% of the subjects (patients with cystic fibrosis [CF] and healthy subjects), and 32% showed neutralizing ability in an in vitro assay. Nab to AAV have been to show limit AAV transduction in liver (47) and lung (28); however, no such effect was seen in muscle (21), brain (43), and retina (5). Interestingly, the humoral response to AAV may be T-cell dependent; the inhibition of T-cell function using anti-CD4 antibodies prevents Nab formation and allows vector readministration (14, 28, 40).

Cell-mediated responses to AAV vectors have been documented, but this response may be dependent on the route of administration (11) and AAV serotype (67). A potent immune response to AAV-ovalbumin was observed when AAV was administered intraperitoneally, intravenously, or subcutaneously but not when administered intramuscularly. Moreover, AAV-2 has been shown to induce a weak cell-mediated immune response. This may be attributed to AAV inefficiently infecting mature dendritic cells (DC); however, a recent study demonstrated an efficient infection of immature DC and generated a cytotoxic-T-lymphocyte (CTL) response when used in adoptive transfer experiments (77). The extent to which mature and immature DC are transduced by AAV in vivo and the mechanism of how AAV induces a cellular immune response are not known.

In a recent clinical trial for hemophilia B, an unexpected liver toxicity was observed and was attributed to a CTL response to AAV-2-transduced hepatocytes (42). Subsequently, it was discovered that the AAV-2 capsid heparin binding motif was responsible for T-cell activation (65). This correlated well with a study in mice that showed that AAV-2 infection can activate a CTL response, whereas AAV-7 and AAV-8 do not (67). Moreover, Wang et al. (67) suggested that the cross-presentation of input AAV capsids via major histocompatibility complex class I presentation may be playing a role in the observed activation of cytotoxic T cells; however, this response does not diminish transgene expression via the targeted destruction of transduced hepatocytes, a finding confirmed by another group (38). Taken together, these studies suggest that immune responses are a major hurdle and that a deeper understanding of AAV-host interactions in humans is required for the efficient use of AAV as a gene transfer vector.

AAV has become increasingly common as a vector for use in human clinical trials; as of now, 38 protocols have been approved by the Recombinant DNA Advisory Committee and the Food and Drug Administration (FDA). The increased popularity of AAV vectors reflects the appreciation of the long-term transgene expression observed in animal models and the relative lack of immune response and other toxicities in the models. Other factors that have played a role in encouraging the use of AAV vectors include the discovery of new serotypes and the appreciation that matching the tissue specificity of the serotype with the presumptive target tissue can greatly enhance the potential effectiveness of therapy. In general, the goal of gene therapy can be classified into one of two categories, the correction of an intracellular defect or the synthesis of a secreted protein, which is active at an extracellular level. In the latter case, the site of protein synthesis would not seem to be critical as long as it has no deleterious intracellular effects and is successfully secreted into blood. This assumption has been tested in clinical trials in which proteins normally synthesized in the liver are now induced to be produced in skeletal muscle. Whether the assumption is correct is still not certain, in part because different vector target sites may induce different host immune responses (41, 42).

Despite the small packaging capacity of AAV vectors, clever investigators have devised ways of engineering transgenes and associated regulatory sequences so that their sizes can be reduced sufficiently to allow packaging into AAV capsids. In general, the expectations with regard to minimal toxicity have been met, although there have been two notable exceptions to this, which will be discussed below. To date, no clinical cures have been effected, although there have been anecdotal data that have kept hopes up. Trials that have been concluded or are in progress are listed in Table . Several of these will be discussed below in some detail to illustrate specific points of interest and concern.

Clinical trials involving AAV vectors

Initial targets for gene therapy included monogenic diseases in which the gene product either was altered to become nonfunctional or was missing. First among these was CF, a lethal, autosomal recessive disease in which the CF transmembrane regulator (CFTR) is inactivated by mutation. CFTR is a component of the Cl channel and the lack of functional CFTR affects the transmembrane electrical potential. This leads to the accumulation of thick secretions in the lung coupled with a loss of the normal respiratory epithelial ciliary activity. The primary difficulty is pulmonary, with an increased incidence of pulmonary infection, especially by Pseudomonas aeruginosa. Additional difficulty occurs with pancreatic secretion, but the loss of the pancreatic enzymes can be treated with supplements. Thirteen protocols have been approved for phase I and phase II clinical trials using an AAV vector (2, 22, 23, 46, 66). Delivery of the vector was achieved by bronchoscope or by aerosol into the lung and in several cases by delivery to the maxillary sinus (to make measurement of the transmembrane potential, which is affected in CF, possible). The primary and most important observation in early trials was the lack of measurable toxicity and a very modest immune response evoked by the route of pulmonary delivery. Serum antibody was evoked but did not affect the subsequent administration of the vector. The measurement of efficacy in the lung is pretty much restricted to measures of pulmonary function; any improvement that was noted in this manner was not statistically significant. However, in those patients who had vector instilled into the maxillary sinus, it was possible to make a somewhat more direct measurement. The most notable effect was an increase in levels of interleukin-10, a cytokine that is anti-inflammatory, and a concomitant decrease in levels of interleukin-8, which has the opposite effect. Major challenges with vector delivery to the lung through the airway included rapid, regular shedding of the respiratory epithelium, which means that cells that have taken up the vector are fairly quickly lost and that the uptake of the AAV-2 vector in cell culture was mostly through the basolateral surface, which is not very accessible via the airway. Thus, consideration must be given to alternative routes of delivery and the possibility of vectors with alternative serotypes.

A second monogenic disease that could be amenable to gene therapy is hemophilia. Although this disease can be lethal, it is functionally chronic with current modes of therapy. The two common forms are hemophilia A and hemophilia B. Clotting requires a complex series of enzymatic reactions. Two of the required enzymes are factors VIII and IX; a lack of the former results in hemophilia A, and a lack of the latter results in hemophilia B. Initial efforts concentrated on the replacement of factor IX, because the coding region and regulatory sequences could readily be encapsidated in the AAV vector. A factor IX AAV vector could be used to cure mice with hemophilia B (31) and, more excitingly, also performed well in a canine model of hemophilia (32). Initial phase I studies were performed by the intramuscular injection of an AAV-2 vector (36, 41). Disappointingly, although no vector toxicity was noted, no transgenic factor IX could be detected in serum. The notion had been that although factor IX is normally expressed in hepatocytes, the expression of factor IX, which could be excreted, in muscle cells could raise serum factor IX concentration to a therapeutic level (10% of normal). The consequence of the failure to see a rise in the factor IX serum level was to alter the vector target to the liver, the normal site of synthesis, with administration via the hepatic artery (42). Vector was administered to the patients in increasing amounts. At the first two doses, there was no detectable toxicity nor any detectable transgenic factor IX in the serum. At the highest dose (2 1012 vector genomes/kg), there was detectable transgenic factor IX in the serum for 4 to 9 weeks in the two subjects. However, in contrast to what was observed in animal models, the serum concentration went back to baseline levels. More troublesome was a rise in liver transaminases in the serum, a sign of liver inflammation. Subsequently, the inflammatory response was shown to be caused by the induction of a CTL response (45). The first question was whether the immune response was due to the transgene product or the vector. It turned out to be due to the AAV capsid. While an antibody response to capsid had been anticipated, the CTL response to AAV proteins had not been anticipated, because all AAV genes had been deleted from the vector. The working hypothesis is that at the highest dose, where the inflammatory response had occurred, the multiplicity of infection (MOI) was sufficiently high that degradation products of the capsid were displayed on the surface of the transduced hepatocytes in sufficient quantity to induce the CTL response. Thus, there is a conundrum: with the vectors used, the dose required to produce a detectable level of factor IX was also sufficient to induce a CTL response, which destroyed the cells expressing factor IX. Possible solutions to this problem include being able to induce tolerance to the AAV capsid fragments displayed on the surface of the hepatocytes or developing a more efficient vector, which would enable a much lower MOI or dose so that a CTL response would not be evoked. The latter may be able to be achieved by use of alternative AAV serotypes such as AAV-8 or by modification of the surface of the AAV capsid to render trafficking of the ingested AAV particle to the cell nucleus, with ensuing expression of the transgene being much more efficient. An example of the latter approach will be described below in the section on future prospects for AAV vectors.

A much more serious problem arose in a clinical trial involving rheumatoid arthritis (33, 70). Rheumatoid arthritis is a disabling inflammatory disease in which the immune system reacts against the body's joint tissue. Current therapy involves blocking the host response against itself. One way of achieving this inhibition is to counteract the effects of the cytokine tumor necrosis factor alpha (TNF-) by use of the drug adalimumab (Humira). Repeated use of the drug is required whenever there is an exacerbation of the disease in a particular joint. An alternative approach would be to design an AAV vector that could express a TNF inhibitor for an extended period of time, with expression located primarily in the joint that had the vector injected. Promising data were achieved in the animal model of disease. Unfortunately, in the phase I clinical trial, one patient became extremely ill the day after the administration of the AAV vector and died within 4 days. Subsequent investigation established that the patient had died of an overwhelming Histoplasmosis capsulatum fungal infection. The patient had also been treated with adalimumab, one of whose side effects is known to be sepsis. Thus, the question was what role, if any, that the AAV vector played in the demise of the patient. While this was studied, the clinical trial was put on hold by the FDA. The study showed that the patient had already had a systemic histoplasmosis infection before the injection of the vector and that this infection was not controlled, most probably because of adalimumab, which is a systemic drug. Among the conclusions of the investigation was that the AAV vector carrying the transgene had not contributed to any toxicity. The possibility remained that the TNF- inhibitor expressed from the transgene might have contributed to a reduction in the ability of the host immune system to combat the infection; this was deemed to be highly unlikely because little, if any, of the vector was able to be detected outside of the joint that had been injected. Thus, in a relatively short period of time, the FDA essentially exonerated the AAV vector and permitted the clinical trial to resume.

Parkinson's disease, a chronic neurodegenerative disease, has also been an area in which there has been an AAV clinical trial. In Parkinson's disease, a loss of dopaminergic neurons leads to the loss of inhibitory gamma aminobutyric acid-sensitive input to the subthalamic nucleus. Kaplitt et al. (34) and Feigin et al. (17) described a study in which 12 patients with advanced Parkinson's disease had an AAV vector carrying a transgene encoding glutamic acid decarboxylase injected into the subthalamic nucleus on one side. The therapy was well tolerated, with no adverse effects attributable to gene therapy noted for any of the patients, who had been divided into three groups that received low, moderate, or high doses of the vector. The clinical impression was that motor activity on the treated side was improved significantly relative to the untreated side regardless of dose. No change in cognition was noted. The clinical impression was supported by position emission tomography scan data, which measured the reduced metabolic activity on the treated side, consistent with enhanced inhibition. Of particular interest was that motor improvement was not noted until 3 months postinjection so that it did not seem directly related to trauma associated with the injection. Also very encouraging was that the observed improvement in motor activity persisted for at least 1 year. Although the trial involved an open surgical procedure, the dramatic improvements noted, if consistent and reproducible, suggest that AAV gene therapy for chronic, degenerative neurological diseases has great promise. Additional clinical trials for Parkinson's disease, Alzheimer's disease, and Batten disease have been approved.

From these three examples of the 38 clinical trials that have been approved, two approaches can be noted. On one hand, the original notion of replacing a defective gene in a monogenic disease is exemplified by the trials involving patients with CF or hemophilia B. The second approach is demonstrated in the Parkinson's disease trial, in which the intention was to block the consequences of a chronic disease characterized more by a metabolic defect caused by the lack of dopaminergic neurons rather than a cure of the primary lesion.

Two inferences can be drawn from those clinical trials that have already been done. The first is that there has been relatively little toxicity that can be directly attributed to the AAV vector platform. The one area of potential toxicity appears to arise from an inflammatory response involving cytotoxic T cells responding to fragments of the coat proteins from input vector that are presented on the cell surface as major histocompatibility complexes. This has been observed when very high doses of vector were given via the hepatic artery or by intramuscular injection. It is a particularly complex reaction, because dosage, location of injection, and the possibility of induction of tolerance all have to be taken into consideration. Humoral immunity seems to play a role in some instances when the subsequent administration of a vector may be blocked, but toxicity per se has not been a significant observation. Again, the route of administration seems to be important; little humoral immunity has been noted when the pulmonary route is used. The ability of humoral antibody to block vector activity is significant because the seropositivity of the population to AAV is high (80 to 90% for AAV-2). However, the discovery of many new AAV serotypes and the ability to package the AAV-2-based vector DNA into many, if not most, of them suggest that preexisting humoral immunity will not pose a significant barrier to therapy.

Although significant progress has been made in the use of AAV vectors for human gene therapy, several developments are likely to enhance the potential utility of the system. The host immune response remains of concern so that approaches to mitigate the response would constitute a definite advance. One such approach would be to reduce the vector dose required for a therapeutic response. The discovery of additional AAV serotypes is one possibility (24). Another is to modify the surface of the vector capsid to include specific ligands for attachment to target tissues (see Rational Design of AAV Capsids). Recently, an alternative approach was described by Srivastava et al. (79). The particle-to-infectivity ratio of AAV vector preparations usually ranges from 10:1 to 100:1. These ratios reflect, in part, incomplete or empty vector particles. However, an additional reason for the high ratios includes trafficking from the endocytoplasmic vesicle to the nucleus. In the course of trafficking, the vector particle may become ubiquitinated and thus directed to a proteasome for degradation rather than to the nucleus, where the transgene may be expressed. Srivastava's group found that ubiquitinylation and direction to the proteasome require the phosphorylation of tyrosine residues on the surface of the vector capsid. There are seven tyrosines on the surface of the AAV-2 capsid, and Srivastava et al. (A. Srivastava et al., unpublished data) systematically replaced each of these tyrosine residues with phenylalanine. The consequence of these modifications is that the MOI required for the detection of transgene expression has been greatly reduced, both in cell culture and in several mouse models of transduction of cells in the liver and eye. This innovation is likely to greatly enhance the ability to increase transgene expression in several diseases to therapeutic levels.

One of the most attractive features of current AAV vectors is the continued expression of the transgene for prolonged periods of time. This is in spite of the extrachromosomal location of the vector. However, the infrequent integration of the vector means that transduction must occur in cells that either do not turn over or do so very slowly. Additionally, the rarity of integration reduces the likelihood of insertional mutagenesis, but the possibility does remain. Recent experience with the induction of leukemia in patients in two clinical trials who were successfully treated for severe combined immunodeficiency disease with retroviral vectors has heightened awareness of the problem (20). Although AAV vectors seem to be highly unlikely to cause such problems in postmitotic tissues, the issue remains of some concern. In contrast to the wild-type AAV genomes, recombinant AAV vector genomes do not integrate site specifically into chromosome 19 in human cells in vitro and have been shown to remain episomal in animal models in vivo. However, all previous studies were carried out with cells and tissues that are postmitotic. In hematopoietic stem cells, which must proliferate and differentiate to give rise to progenitor cells, recombinant AAV genomes would be lost in the absence of stable integration into chromosomal DNA. Srivastava and colleagues, using a murine bone marrow serial transplant model in vivo, documented the stable integration of the proviral genomes, and integration sites were localized to different mouse chromosomes (A. Srivastava et al., unpublished data). None of the integration sites was found to be in a transcribed gene or near a cellular oncogene. All animals monitored for up to 1 year exhibited no pathological abnormalities. Thus, an AAV proviral integration-induced risk of oncogenesis was not found in these studies.

One of the features of AAV is its ability to specifically integrate into chromosome 19q13.4 to establish latent infection. Current AAV vectors do not have this ability because they lack both the cis-active signal in P5 (IEE) and the trans-active proteins (Rep68 and Rep78) required for site-specific integration. The development of such a vector would enable the transduction of germ or progenitor cells and thus help to ensure long-term transgene expression in tissues where cell turnover is a consideration. If transduction were done ex vivo, it would theoretically be possible to clone cells in which site-specific integration had occurred in the absence of significant, additional random integration. Appropriate vector design would allow the rep gene to be expressed during transduction but not itself be incorporated. Two such vectors were described: one is an AAV/adenovirus hybrid (54), and the other is a bipartite AAV vector (78). In the latter case, Rep is expressed from one component, and the second component contains the cis-active IEE. Both systems are promising but in early stages of development.

Another area with great potential for improvement is the route of administration. This is particularly true for the use of AAV vectors in the central nervous system (CNS). Currently, vector administration requires an open neurosurgical procedure. This is true because of the blood-brain barrier and because of the desire to target specific areas of the CNS. The development of vectors that could achieve the required targeting specificity and the ability to penetrate the blood-brain barrier would greatly facilitate CNS gene therapy. A number of different methods have been suggested and tried with limited success to date.

Other possible advances include a better understanding of the host response and the requirements for the induction of tolerance and the development of more efficient systems for the production of AAV vectors (12).

Gene therapy requires three things: the identification of the defect at the molecular level, a correcting gene, and a way to introduce the gene into appropriate host cells (i.e., a vector). We now have a sophisticated understanding of the basic mechanisms of many genetic diseases, and many corresponding genes have been cloned and can be produced at high levels. The major hurdle to be surmounted is the development of adequate vectors. The wide variety of approaches that have been tried, many of which are still being studied, points to the challenge of developing effective vectors. The delivery methods that have been tried include purified DNA under hydrodynamic pressure, the shotgun approach using DNA adhering to gold particles, lipid-DNA complexes, and, finally, virus-based vectors. Although the first three methods have an inherent simplicity that is attractive, in practice, the efficiency of gene delivery and expression has been lower than what is required for therapeutic efficacy. Viruses, on the other hand, represent nature's vectors for the delivery and expression of exogenous genes in host cells. Here, the challenge is to maintain the efficiency of delivery and expression while minimizing any pathogenicity of the virus from which the vector was derived. In practice, the challenge has been significant. In the only clearly documented instance of therapeutic correction of an inborn error, the inherent oncogenic properties of the original virus (Moloney murine leukemia virus) were retained; 4 of 12 patients with X-linked severe combined immunodeficiency disease developed leukemia. In this experiment, bone marrow precursor cells were transduced and allowed to differentiate. Under these conditions, a vector that would integrate was needed.

Among current viral vectors, only those derived from retroviruses have the ability to integrate at a reasonable frequency; retroviruses require cell division for integration to occur, whereas lentiviruses and foamy viruses can enter the nucleus and integrate in nondividing cells. Lentiviral vectors carry the psychological burden of being derived from significant pathogens, but foamy viruses infect a high percentage of humans without having been implicated as the cause of disease. Although there are production challenges, very promising results have been obtained in a canine model of congenital granulomatosis. The overriding theoretical consideration is that retroviruses integrate at many sites in the human genome, so there is always the concern of insertional mutagenesis possibly causing oncogenesis.

AAV-2, and presumably other serotypes, has been reported to integrate at a specific site in the q arm of chromosome 19 (AAVS1). The frequency with which integration occurs in AAVS1 has been reported to be from 60 to 90%. This exceeds the frequency that has been observed, with the most successful vectors being derived from bacteriophage systems. However, current AAV vectors do not have this ability (they lack the sequences required both in trans and in cis), and integration, which has been observed to occur at a low frequency (107), is random. As discussed above (Future Prospects), it is possible to design AAV vectors that can integrate in a site-specific manner; therefore, a DNA virus vector is possible.

AAV was initially considered as a vector by only a few laboratories. This undoubtedly reflected the lack of familiarity with the virus, since it is nonpathogenic and, thus, of interest only to those inherently interested in its distinctive biology. However, as noted above, with time, it has become among the most commonly used viral vectors. This is likely the consequence of several factors. First, almost all other viral vectors lead to an initial burst of transgene expression that commonly disappears after a relatively short time, measured in weeks. AAV transgene expression, on the other hand, frequently persists for years or the life time of the animal model. Second, other viral vectors have a greater capacity with which to insert the transgene(s). However, with time and clever engineering, it has been possible to insert originally very large transgenes into AAV vectors. Interestingly, it has also proved to be feasible to have split vectors in which one construct has slight sequence overlap with a second construct so that recombination after vector nuclear entry leads to the intact transgene product being expressed. Thus, the consequences of the small size of the AAV genome have been overcome to a large extent.

Another significant positive feature of AAV vectors is that they frequently do not elicit a deleterious immune response. This feature is dependent on the site of administration and the effective MOI of the vector used. Another factor is that AAV appears to be taken up poorly by dendritic cells. Finally, the small capacity of the genome has meant that no viral genes remain. In a parallel manner, the latest version of adenovirus vectors is the gutless vectors from which all viral genes have also been removed. Interestingly, the gutless adenovirus vectors still do not perform as well as AAV vectors in terms of expression persistence. It is tempting to speculate that the difference reflects the special structure of the AAV ITR, which could serve both as an insulator and to protect against cellular exonucleases.

Thus, AAV has become appreciated as a good vector for the transduction of postmitotic cells. At this time, retroviral vectors remain the vector of choice for the transduction of stem or progenitor cells despite the inherent concern of possible oncogenesis. These considerations apply for situations in which long-term transgene expression is desired. In cases such as immunization or vector-induced oncolysis, where expression at higher levels for relatively short periods of time is desirable, other viral vectors such as those derived from adenovirus and herpesvirus have more useful characteristics. What has become apparent is that different vectors have characteristics that are advantageous in specific cases. Thus, the notion of best vector depends on the question of what is best for what purpose.

AAV remains a promising delivery system for the realization of the dream of gene therapy. It compares favorably to other viral vectors, especially when sustained transgene expression is desired. Although nonviral vector systems such as lipid-mediated vectors, hydrodynamic delivery, and the gene gun have been advocated and tried, to date, none have approached the efficacy of the viral delivery systems. Whether such development will occur remains unknown. AAV vectors have achieved some success, and it seems likely that some of the advances described above and others not yet envisioned will enable AAV to become an effective therapeutic agent.

We thank A. Srivastava for his helpful suggestions.

The work was supported in part by a grant from the USPHS, grant DK58327.

Articles from Clinical Microbiology Reviews are provided here courtesy of American Society for Microbiology (ASM)

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Gene Therapy Using Adeno-Associated Virus Vectors

What Do We Make?

Gene Tools makes Morpholino antisense oligos. Morpholino oligos bind to complementary RNA and get in the way of processes; they can knock down gene expression, modify RNA splicing or inhibit miRNA activity and maturation. Morpholinos are the premier knockdown tools used in developmental biology labs, the best RNA-blocking reagents for cells in culture and, as Vivo-Morpholinos, the most specific delivery-enhanced oligos available for other animal models. We are the sole commercial manufacturer selling research quantities of Morpholinos world-wide.

Morpholino oligos are short chains of about 25 Morpholino subunits. Each subunit is comprised of a nucleic acid base, a morpholine ring and a non-ionic phosphorodiamidate intersubunit linkage. Morpholinos do not degrade their RNA targets, but instead act via an RNAse H-independent steric blocking mechanism. With their requirement for greater complementarity with their target RNAs, Morpholinos are free of the widespread off-target expression modulation typical of knockdowns which rely on RISC or RNase-H activity. They are completely stable in cells and do not induce immune responses.

With their high mRNA binding affinity and exquisite specificity, Morpholinos yield reliable and predictable results. Depending on the oligo sequence selected, they either can block translation initiation in the cytosol (by targeting the 5' UTR through the first 25 bases of coding sequence), can modify pre-mRNA splicing in the nucleus (by targeting splice junctions or splice regulatory sites) or can inhibit miRNA maturation and activity (by targeting pri-miRNA or mature miRNA), as well as more exotic applications such as ribozyme inhibition, modifying poly-A tailing, blocking RNA translocation sequences or translational frameshifting. Morpholinos have been shown effective in animals, protists, plants and bacteria.

We are continually developing novel cytosolic delivery systems like our 'Endo-Porter' for cultured cells and our Vivo-Morpholinos for both cultures and in vivo delivery. With established delivery technologies it's easy to deliver Morpholinos into cultures, embryos or animals -- making Morpholinos the best tools for genetic studies and drug target validation programs.

What Sets Us Apart?

Morpholino oligos have excellent antisense properties compared to other gene knockdown systems. Microinjection or electroporation of Morpholino oligos into the embryos of frogs, zebrafish, chicks, sea urchins and other organisms successfully and specifically shuts down the expression of targeted genes, making Morpholinos an indispensable tool of developmental biologists. Morpholinos have also proven their versatility and efficacy in cultures of primary or immortal cells when delivered by Endo-Porter, electroporation or Vivo-Morpholinos. Usually, Vivo-Morpholinos are used to bring the specificity and efficacy of Morpholino oligos to experiments requiring systemic delivery in adult animals. The list of over 7500 publications using Morpholinos is growing daily and is maintained on-line in a browseable database.

Besides providing the best knockdown and splice modification tools, we also provide the best customer support available in the gene silencing industry. Our customer support team includes three Ph.D.-level scientists with hands-on Morpholino experience who are available to: 1) discuss your experiment design, 2) design your oligos for you, and 3) help you troubleshoot your experiments, all at no additional cost.

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What are targeted cancer therapies?

Targeted cancer therapies are drugs or other substances that block the growth and spread of cancer by interfering with specific molecules ("molecular targets") that are involved in the growth, progression, and spread of cancer. Targeted cancer therapies are sometimes called "molecularly targeted drugs," "molecularly targeted therapies," "precision medicines," or similar names.

Targeted therapies differ from standard chemotherapy in several ways:

Targeted therapies are currently the focus of much anticancer drug development. They are a cornerstone of precision medicine, a form of medicine that uses information about a persons genes and proteins to prevent, diagnose, and treat disease.

Many targeted cancer therapies have been approved by the Food and Drug Administration (FDA) to treat specific types of cancer. Others are being studied in clinical trials (research studies with people), and many more are in preclinical testing (research studies with animals).

The development of targeted therapies requires the identification of good targetsthat is, targets that play a key role in cancer cell growth and survival. (It is for this reason that targeted therapies are sometimes referred to as the product of "rational" drug design.)

One approach to identify potential targets is to compare the amounts of individual proteins in cancer cells with those in normal cells. Proteins that are present in cancer cells but not normal cells or that are more abundant in cancer cells would be potential targets, especially if they are known to be involved in cell growth or survival. An example of such a differentially expressed target is the human epidermal growth factor receptor 2 protein (HER-2). HER-2 is expressed at high levels on the surface of some cancer cells. Several targeted therapies are directed against HER-2, including trastuzumab (Herceptin), which is approved to treat certain breast and stomach cancers that overexpress HER-2.

Another approach to identify potential targets is to determine whether cancer cells produce mutant (altered) proteins that drive cancer progression. For example, the cell growth signaling protein BRAF is present in an altered form (known as BRAF V600E) in many melanomas. Vemurafenib (Zelboraf) targets this mutant form of the BRAF protein and is approved to treat patients with inoperable or metastatic melanoma that contains this altered BRAF protein.

Researchers also look for abnormalities in chromosomes that are present in cancer cells but not in normal cells. Sometimes these chromosome abnormalities result in the creation of a fusion gene (a gene that incorporates parts of two different genes) whose product, called a fusion protein, may drive cancer development. Such fusion proteins are potential targets for targeted cancer therapies. For example, imatinib mesylate (Gleevec) targets the BCR-ABL fusion protein, which is made from pieces of two genes that get joined together in some leukemia cells and promotes the growth of leukemic cells.

How are targeted therapies developed?

Once a candidate target has been identified, the next step is to develop a therapy that affects the target in a way that interferes with its ability to promote cancer cell growth or survival. For example, a targeted therapy could reduce the activity of the target or prevent it from binding to a receptor that it normally activates, among other possible mechanisms.

Most targeted therapies are either small molecules or monoclonal antibodies. Small-molecule compounds are typically developed for targets that are located inside the cell because such agents are able to enter cells relatively easily. Monoclonal antibodies are relatively large and generally cannot enter cells, so they are used only for targets that are outside cells or on the cell surface.

Candidate small molecules are usually identified in what are known as "high-throughput screens," in which the effects of thousands of test compounds on a specific target protein are examined. Compounds that affect the target (sometimes called "lead compounds") are then chemically modified to produce numerous closely related versions of the lead compound. These related compounds are then tested to determine which are most effective and have the fewest effects on nontarget molecules.

Monoclonal antibodies are developed by injecting animals (usually mice) with purified target proteins, causing the animals to make many different types of antibodies against the target. These antibodies are then tested to find the ones that bind best to the target without binding to nontarget proteins.

Before monoclonal antibodies are used in humans, they are "humanized" by replacing as much of the mouse antibody molecule as possible with corresponding portions of human antibodies. Humanizing is necessary to prevent the human immune system from recognizing the monoclonal antibody as "foreign" and destroying it before it has a chance to bind to its target protein. Humanization is not an issue for small-molecule compounds because they are not typically recognized by the body as foreign.

What types of targeted therapies are available?

Many different targeted therapies have been approved for use in cancer treatment. These therapies include hormone therapies, signal transduction inhibitors, gene expression modulators, apoptosis inducers, angiogenesis inhibitors, immunotherapies, and toxin delivery molecules.

Cancer vaccines and gene therapy are sometimes considered targeted therapies because they interfere with the growth of specific cancer cells. Information about these treatments can be found in the NCI fact sheets Cancer Vaccines and Biological Therapies for Cancer.

How is it determined whether a patient is a candidate for targeted therapy?

For some types of cancer, most patients with that cancer will have an appropriate target for a particular targeted therapy and, thus, will be candidates to be treated with that therapy. CML is an example: most patients have the BCR-ABL fusion gene. For other cancer types, however, a patients tumor tissue must be tested to determine whether or not an appropriate target is present. The use of a targeted therapy may be restricted to patients whose tumor has a specific gene mutation that codes for the target; patients who do not have the mutation would not be candidates because the therapy would have nothing to target.

Sometimes, a patient is a candidate for a targeted therapy only if he or she meets specific criteria (for example, their cancer did not respond to other therapies, has spread, or is inoperable). These criteria are set by the FDA when it approves a specific targeted therapy.

Targeted therapies do have some limitations. One is that cancer cells can become resistant to them. Resistance can occur in two ways: the target itself changes through mutation so that the targeted therapy no longer interacts well with it, and/or the tumor finds a new pathway to achieve tumor growth that does not depend on the target.

For this reason, targeted therapies may work best in combination. For example, a recent study found that using two therapies that target different parts of the cell signaling pathway that is altered in melanoma by the BRAF V600E mutation slowed the development of resistance and disease progression to a greater extent than using just one targeted therapy (1).

Another approach is to use a targeted therapy in combination with one or more traditional chemotherapy drugs. For example, the targeted therapy trastuzumab (Herceptin) has been used in combination with docetaxel, a traditional chemotherapy drug, to treat women with metastatic breast cancer that overexpresses the protein HER2/neu.

Another limitation of targeted therapy at present is that drugs for some identified targets are difficult to develop because of the targets structure and/or the way its function is regulated in the cell. One example is Ras, a signaling protein that is mutated in as many as one-quarter of all cancers (and in the majority of certain cancer types, such as pancreatic cancer). To date, it has not been possible to develop inhibitors of Ras signaling with existing drug development technologies. However, promising new approaches are offering hope that this limitation can soon be overcome.

What are the side effects of targeted cancer therapies?

Scientists had expected that targeted cancer therapies would be less toxic than traditional chemotherapy drugs because cancer cells are more dependent on the targets than are normal cells. However, targeted cancer therapies can have substantial side effects.

The most common side effects seen with targeted therapies are diarrhea and liver problems, such as hepatitis and elevated liver enzymes. Other side effects seen with targeted therapies include:

Certain side effects of some targeted therapies have been linked to better patient outcomes. For example, patients who develop acneiform rash (skin eruptions that resemble acne) while being treated with the signal transduction inhibitors erlotinib (Tarceva) or gefitinib (Iressa), both of which target the epidermal growth factor receptor, have tended to respond better to these drugs than patients who do not develop the rash (2). Similarly, patients who develop high blood pressure while being treated with the angiogenesis inhibitor bevacizumab generally have had better outcomes (3).

The few targeted therapies that are approved for use in children can have different side effects in children than in adults, including immunosuppression and impaired sperm production (4).

What targeted therapies have been approved for specific types of cancer?

The FDA has approved targeted therapies for the treatment of some patients with the following types of cancer (some targeted therapies have been approved to treat more than one type of cancer):

Adenocarcinoma of the stomach or gastroesophageal junction: Trastuzumab (Herceptin), ramucirumab (Cyramza)

Basal cell carcinoma: Vismodegib (Erivedge), sonidegib (Odomzo)

Bladder cancer: Atezolizumab (Tecentriq)

Brain cancer: Bevacizumab (Avastin), everolimus (Afinitor)

Breast cancer: Everolimus (Afinitor), tamoxifen (Nolvadex), toremifene (Fareston), Trastuzumab (Herceptin), fulvestrant (Faslodex), anastrozole (Arimidex), exemestane (Aromasin), lapatinib (Tykerb), letrozole (Femara), pertuzumab (Perjeta), ado-trastuzumab emtansine (Kadcyla), palbociclib (Ibrance)

Cervical cancer: Bevacizumab (Avastin)

Colorectal cancer: Cetuximab (Erbitux), panitumumab (Vectibix), bevacizumab (Avastin), ziv-aflibercept (Zaltrap), regorafenib (Stivarga), ramucirumab (Cyramza)

Dermatofibrosarcoma protuberans: Imatinib mesylate (Gleevec)

Endocrine/neuroendocrine tumors: Lanreotide acetate (Somatuline Depot)

Head and neck cancer: Cetuximab (Erbitux)

Gastrointestinal stromal tumor: Imatinib mesylate (Gleevec), sunitinib (Sutent), regorafenib (Stivarga)

Giant cell tumor of the bone: Denosumab (Xgeva)

Kaposi sarcoma: Alitretinoin (Panretin)

Kidney cancer: Bevacizumab (Avastin), sorafenib (Nexavar), sunitinib (Sutent), pazopanib (Votrient), temsirolimus (Torisel), everolimus (Afinitor), axitinib (Inlyta), nivolumab (Opdivo),cabozantinib (Cabometyx), lenvatinib mesylate (Lenvima)

Leukemia: Tretinoin (Vesanoid), imatinib mesylate (Gleevec), dasatinib (Sprycel), nilotinib (Tasigna), bosutinib (Bosulif), rituximab (Rituxan), alemtuzumab (Campath), ofatumumab (Arzerra), obinutuzumab (Gazyva), ibrutinib (Imbruvica), idelalisib (Zydelig), blinatumomab (Blincyto), venetoclax (Venclexta)

Liver cancer: Sorafenib (Nexavar)

Lung cancer: Bevacizumab (Avastin), crizotinib (Xalkori), erlotinib (Tarceva), gefitinib (Iressa), afatinib dimaleate (Gilotrif), ceritinib (LDK378/Zykadia), ramucirumab (Cyramza), nivolumab (Opdivo), pembrolizumab (Keytruda), osimertinib (Tagrisso), necitumumab (Portrazza), alectinib (Alecensa)

Lymphoma: Ibritumomab tiuxetan (Zevalin), denileukin diftitox (Ontak), brentuximab vedotin (Adcetris), rituximab (Rituxan), vorinostat (Zolinza), romidepsin (Istodax), bexarotene (Targretin), bortezomib (Velcade), pralatrexate (Folotyn),ibrutinib (Imbruvica), siltuximab (Sylvant), idelalisib (Zydelig), belinostat (Beleodaq), obinutuzumab (Gazyva), nivolumab (Opdivo)

Melanoma: Ipilimumab (Yervoy), vemurafenib (Zelboraf), trametinib (Mekinist), dabrafenib (Tafinlar), pembrolizumab (Keytruda), nivolumab (Opdivo), cobimetinib (Cotellic)

Multiple myeloma: Bortezomib (Velcade), carfilzomib (Kyprolis),panobinostat (Farydak), daratumumab (Darzalex), ixazomib citrate (Ninlaro), elotuzumab (Empliciti)

Myelodysplastic/myeloproliferative disorders: Imatinib mesylate (Gleevec), ruxolitinib phosphate (Jakafi)

Neuroblastoma: Dinutuximab (Unituxin)

Ovarian epithelial/fallopian tube/primary peritoneal cancers: Bevacizumab (Avastin), olaparib (Lynparza)

Pancreatic cancer: Erlotinib (Tarceva), everolimus (Afinitor), sunitinib (Sutent)

Prostate cancer: Cabazitaxel (Jevtana), enzalutamide (Xtandi), abiraterone acetate (Zytiga), radium 223 dichloride (Xofigo)

Soft tissue sarcoma: Pazopanib (Votrient)

Systemic mastocytosis: Imatinib mesylate (Gleevec)

Thyroid cancer: Cabozantinib (Cometriq), vandetanib (Caprelsa), sorafenib (Nexavar), lenvatinib mesylate (Lenvima)

Where can I find information about clinical trials of targeted therapies?

Follow this link:
Targeted Cancer Therapies Fact Sheet - National Cancer ...

Gene Therapy- An Overview

Gene Therapy is a processin which faulty genes are rectified by the use of several different techniques. The idea of Gene Therapy was coined in the 1950s almost directly after Watson and Crick discovery of unwinding the DNA double-helix. Scientists worked diligently, playing with the idea of being able to insert healthy genes in place of mutated ones which cause severe genetic disease.

According Anne Matthews, RN, phD, director of Genetic Counseling and Family Studies, statistics have shown that "approximately 4 million babies are born each year. About 3 to 4% will be born with a genetic disease or major birth defect."(Citation 8) These unpreventable and seemingly incurable genetic diseases are generally malicious, causing debilitating effects on the individuals as well as theirfamilies. Desperate for a cure, doctors and scientists experimented with many different methods, eventually discovering gene therapy.

This therapy is relatively new, so much research is still being done. Like all new medical techniques, the ethics of Gene Therapy are highly debated. While some people argue for Gene Therapy as a innovative new life-saving method, others believe that humans should have no role in tampering with natural creation. As of now there is no FDA (US Food and Drug Administration) regulated treatment or product that is for sale. However, research by top scientist and labs continue to experiment with over 400 clinical trials conducted in the United States. In thecomingyears scientist hope to test the vastopportunitiesthat gene therapy offers and make it anaccessibletreatment.

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Gene Therapy

Validation of Screening Tool for ROS1 Gene Rearrangements May 11, 2016 Immunohistochemistry (IHC) is an effective tool that can be used for identifying proto-oncogene 1 receptor tyrosine kinase (ROS1) gene rearrangements and screening patients for the administration of ... read more New Study Shows Children Benefited Most from Gene Therapy for LCA, a Rare Eye Disease Apr. 15, 2016 Scientists have completed a two-year Phase I clinical trial which showed that children showed the greatest benefit from gene therapy for treatment of Leber congenital amaurosis or severe early ... read more Novel Mechanism of Crizotinib Resistance in a ROS1+ NSCLC Patient Apr. 11, 2016 Molecular analysis of a tumor biopsy from a proto-oncogene 1 receptor tyrosine kinase positive (ROS1+) patient with acquired crizotinib resistance revealed a novel mutation in the v-kit Hardy ... read more Mar. 24, 2016 Two new gene modification methods have been developed: lsODN (long single-stranded oligodeoxynucleotide) and 2H2OP (two-hit two-oligo with plasmid).These methods use CRISPR (Clustered Regularly ... read more Mar. 10, 2016 Neurons in the brain that have been supplemented with a synthetic gene can be remotely manipulated by a magnetic field, scientists have shown. The finding has implications for possible future ... read more Modified Form of CRISPR Acts as a Toggle Switch to Control Gene Expression in Stem Cells Mar. 10, 2016 Combining the two most powerful biological tools of the 21st century, scientists have modified how the genome of induced pluripotent stem cells (iPSCs) is read for the first time using a variation of ... read more Scientists Use Synthetic Gene and Magnets to Alter Behavior of Mice, Fish Mar. 7, 2016 Scientists have demonstrated that neurons in the brain that have been supplemented with a synthetic gene can be remotely manipulated by a magnetic field. This has implications for future treatment of ... read more Rare Respiratory Disease Gene Carriers Actually Have Increased Lung Function Mar. 4, 2016 New research has revealed the healthy carriers of a gene that causes a rare respiratory disease are taller and larger than average, with greater respiratory capacity. The disease, alpha1-antitrypsin ... read more Normal Stem Cells Linked to Aggressive Prostate Cancer Feb. 29, 2016 A study that revealed new findings about prostate cells may point to future strategies for treating aggressive and therapy-resistant forms of prostate cancer, report ... read more Feb. 24, 2016 A new treatment for aplastic anemia is based on the transport of the telomerase gene to the bone marrow cells using gene therapy, a completely new strategy in the treatment of aplastic ... read more Potential Treatment for Friedreich's Ataxia Identified Feb. 16, 2016 Researchers have identified synthetic RNA and DNA that reverses the protein deficiency causing Friedreichs ataxia, a neurological disease for which there is currently no ... read more Researchers Identify Way Radiation May Fight Cancer Cells Escaping Immune System Feb. 1, 2016 A team of researchers is fighting cancers using a combination of therapies and recently found ways that radiation could maximize responses to novel immune-based therapeutic approaches to fight ... read more In Lung Cancer, Not All HER2 Alterations Are Created Equal Jan. 28, 2016 Study shows two distinct causes of HER2 activation in lung cancer: mutation of the gene and amplification of the gene. In patient samples of lung adenocarcinoma, 3 percent were found to have HER2 ... read more Gene Therapy for Rare Bleeding Disorder Achieves Proof-of-Concept Jan. 20, 2016 Hematology researchers have used a single injection of gene therapy to correct a rare bleeding disorder, factor VII deficiency, in dogs. This success in large animals holds considerable potential for ... read more Common Gene Mutation Bad for Liver Values, Good for Blood Lipids in Children Jan. 13, 2016 A common mutation in one gene raises liver values but at the same time improves blood lipid values in healthy children, according to a recent study. Children who carry the gene mutation had higher ... read more Novel RNA Delivery System May Treat Incurable Blood Cancers Jan. 5, 2016 Mantle Cell Lymphoma is considered the most aggressive known blood cancer, and available therapies are scarce. A new study offers tangible hope of curing the currently incurable cancer -- and others ... read more Three Hits to Fight Lung Cancer Jan. 4, 2016 Cancers with KRAS-related gene mutations might benefit from a triple therapy with two experimental drugs plus radiation therapy, a new study in mice has ... read more Dec. 16, 2015 Proteins are like bricks that form our cells and they are built by the orders given by our genetic material, DNA. In human diseases, eventually DNA alterations modify proteins and they don't do ... read more Dec. 12, 2015 Results from a long-term clinical trial conducted by cancer researchers show that combining radiation treatment with 'suicide gene therapy' provides a safe and effective one-two punch ... read more Gene Therapy Used to Extend Estrogen's Protective Effects on Memory Dec. 8, 2015 The hormone estrogen helps protect memory and promote a healthy brain, but this effect wanes as women age, and even estrogen replacement therapy stops working in humans after age 65. Now researchers ... read more

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The rest is here:
Gene Therapy News -- ScienceDaily

Please choose from the following list of questions for information about gene therapy, an experimental technique that uses genetic material to treat or prevent disease.

On this page:

Gene therapy is an experimental technique that uses genes to treat or prevent disease. In the future, this technique may allow doctors to treat a disorder by inserting a gene into a patients cells instead of using drugs or surgery. Researchers are testing several approaches to gene therapy, including:

Replacing a mutated gene that causes disease with a healthy copy of the gene.

Inactivating, or knocking out, a mutated gene that is functioning improperly.

Introducing a new gene into the body to help fight a disease.

Although gene therapy is a promising treatment option for a number of diseases (including inherited disorders, some types of cancer, and certain viral infections), the technique remains risky and is still under study to make sure that it will be safe and effective. Gene therapy is currently only being tested for the treatment of diseases that have no other cures.

MedlinePlus from the National Library of Medicine offers a list of links to information about genes and gene therapy.

Educational resources related to gene therapy are available from GeneEd.

The Genetic Science Learning Center at the University of Utah provides an interactive introduction to gene therapy and a discussion of several diseases for which gene therapy has been successful.

The Centre for Genetics Education provides an introduction to gene therapy, including a discussion of ethical and safety considerations.

KidsHealth from Nemours offers a fact sheet called Gene Therapy and Children.

Additional information about gene therapy is available from the National Genetics and Genomics Education Centre of the National Health Service (UK)

Gene therapy is designed to introduce genetic material into cells to compensate for abnormal genes or to make a beneficial protein. If a mutated gene causes a necessary protein to be faulty or missing, gene therapy may be able to introduce a normal copy of the gene to restore the function of the protein.

A gene that is inserted directly into a cell usually does not function. Instead, a carrier called a vector is genetically engineered to deliver the gene. Certain viruses are often used as vectors because they can deliver the new gene by infecting the cell. The viruses are modified so they cant cause disease when used in people. Some types of virus, such as retroviruses, integrate their genetic material (including the new gene) into a chromosome in the human cell. Other viruses, such as adenoviruses, introduce their DNA into the nucleus of the cell, but the DNA is not integrated into a chromosome.

The vector can be injected or given intravenously (by IV) directly into a specific tissue in the body, where it is taken up by individual cells. Alternately, a sample of the patients cells can be removed and exposed to the vector in a laboratory setting. The cells containing the vector are then returned to the patient. If the treatment is successful, the new gene delivered by the vector will make a functioning protein.

Researchers must overcome many technical challenges before gene therapy will be a practical approach to treating disease. For example, scientists must find better ways to deliver genes and target them to particular cells. They must also ensure that new genes are precisely controlled by the body.

A new gene is injected into an adenovirus vector, which is used to introduce the modified DNA into a human cell. If the treatment is successful, the new gene will make a functional protein.

The Genetic Science Learning Center at the University of Utah provides information about various technical aspects of gene therapy in Gene Delivery: Tools of the Trade. They also discuss other approaches to gene therapy and offer a related learning activity called Space Doctor.

The Better Health Channel from the State Government of Victoria (Australia) provides a brief introduction to gene therapy, including the gene therapy process and delivery techniques.

Penn Medicines Oncolink describes how gene therapy works and how it is administered to patients.

Gene therapy is under study to determine whether it could be used to treat disease. Current research is evaluating the safety of gene therapy; future studies will test whether it is an effective treatment option. Several studies have already shown that this approach can have very serious health risks, such as toxicity, inflammation, and cancer. Because the techniques are relatively new, some of the risks may be unpredictable; however, medical researchers, institutions, and regulatory agencies are working to ensure that gene therapy research is as safe as possible.

Comprehensive federal laws, regulations, and guidelines help protect people who participate in research studies (called clinical trials). The U.S. Food and Drug Administration (FDA) regulates all gene therapy products in the United States and oversees research in this area. Researchers who wish to test an approach in a clinical trial must first obtain permission from the FDA. The FDA has the authority to reject or suspend clinical trials that are suspected of being unsafe for participants.

The National Institutes of Health (NIH) also plays an important role in ensuring the safety of gene therapy research. NIH provides guidelines for investigators and institutions (such as universities and hospitals) to follow when conducting clinical trials with gene therapy. These guidelines state that clinical trials at institutions receiving NIH funding for this type of research must be registered with the NIH Office of Biotechnology Activities. The protocol, or plan, for each clinical trial is then reviewed by the NIH Recombinant DNA Advisory Committee (RAC) to determine whether it raises medical, ethical, or safety issues that warrant further discussion at one of the RACs public meetings.

An Institutional Review Board (IRB) and an Institutional Biosafety Committee (IBC) must approve each gene therapy clinical trial before it can be carried out. An IRB is a committee of scientific and medical advisors and consumers that reviews all research within an institution. An IBC is a group that reviews and approves an institutions potentially hazardous research studies. Multiple levels of evaluation and oversight ensure that safety concerns are a top priority in the planning and carrying out of gene therapy research.

Information about the development of new gene therapies and the FDAs role in overseeing the safety of gene therapy research can be found in the fact sheet Human Gene Therapies: Novel Product Development Q&A.

The Genetic Science Learning Center at the University of Utah explains challenges related to gene therapy.

The NIHs Office of Biotechnology Activities provides NIH guidelines for biosafety.

Because gene therapy involves making changes to the bodys set of basic instructions, it raises many unique ethical concerns. The ethical questions surrounding gene therapy include:

How can good and bad uses of gene therapy be distinguished?

Who decides which traits are normal and which constitute a disability or disorder?

Will the high costs of gene therapy make it available only to the wealthy?

Could the widespread use of gene therapy make society less accepting of people who are different?

Should people be allowed to use gene therapy to enhance basic human traits such as height, intelligence, or athletic ability?

Current gene therapy research has focused on treating individuals by targeting the therapy to body cells such as bone marrow or blood cells. This type of gene therapy cannot be passed on to a persons children. Gene therapy could be targeted to egg and sperm cells (germ cells), however, which would allow the inserted gene to be passed on to future generations. This approach is known as germline gene therapy.

The idea of germline gene therapy is controversial. While it could spare future generations in a family from having a particular genetic disorder, it might affect the development of a fetus in unexpected ways or have long-term side effects that are not yet known. Because people who would be affected by germline gene therapy are not yet born, they cant choose whether to have the treatment. Because of these ethical concerns, the U.S. Government does not allow federal funds to be used for research on germline gene therapy in people.

The National Human Genome Research Institute discusses scientific issues and ethical concerns surrounding germline gene therapy.

A discussion of the ethics of gene therapy and genetic enhancement is available from the University of Missouri Center for Health Ethics.

Gene therapy is currently available only in a research setting. The U.S. Food and Drug Administration (FDA) has not yet approved any gene therapy products for sale in the United States.

Hundreds of research studies (clinical trials) are under way to test gene therapy as a treatment for genetic conditions, cancer, and HIV/AIDS. If you are interested in participating in a clinical trial, talk with your doctor or a genetics professional about how to participate.

You can also search for clinical trials online. ClinicalTrials.gov, a service of the National Institutes of Health, provides easy access to information on clinical trials. You can search for specific trials or browse by condition or trial sponsor. You may wish to refer to a list of gene therapy trials that are accepting (or will accept) participants.

Next: The Human Genome Project

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Gene Therapy - Genetics Home Reference

Posted on: Friday, July 31, 2015 by Nicola Robas

We are a step closer to being able to prevent some types of inherited deafness thanks to ground breaking research showing that gene therapy has been successfully used in mice to restore hearing. Nicola Robas from our Biomedical Research team tells us more.

The instructions for how our bodies develop and function are contained in our genes. We each have small variations in our genetic instructions but most of the time these differences do not alter how a gene functions. However, sometimes the differences can stop a gene from working properly. If this occurs in a gene needed for hearing it can lead to deafness (known as genetic or inherited deafness). So far scientists have identified over 100 genes that can cause genetic hearing loss. While our ability to diagnose genetic hearing loss has vastly improved, the current treatments remain limited to hearing aids and cochlear implants. These devices can be very effective at improving hearing but they cannot help everyone with inherited deafness, and they do not fix the root cause of the hearing loss.

Researchers have been looking at one particular type of inherited hearing loss caused by changes in a gene called TMC1. The protein produced by the TMC1 gene forms part of the machinery in the sound-sensing hair cells of the inner ear that converts mechanical sound waves into electrical signals that are then sent to the brain, allowing us to perceive sound. If TMC1 is not working correctly, then sound signals cannot be sent from the ear to the brain, leading to a hearing loss. In people, changes in TMC1 can cause 2 forms of deafness. In the most common form of TMC1-related deafness, children become profoundly deaf from a very young age, usually around two years old. The second causes children to go deaf gradually from about the age of 10 to 15.

Gene therapy to replace a faulty gene with a normally functioning copy has the potential to prevent certain types of genetic deafness. New research, led by scientists at Harvard Medical School, has shown in mice, that gene therapy can restore the hearing of animals with a faulty TMC1 gene. A virus engineered to produce a healthy copy of this gene was injected into the cochlea of mice in which TMC1 wasnt working correctly (thereby acting as an experimental model of the human form of deafness).

25 days after the injection the mice showed a partial recovery of hearing. The mice went from having a profound hearing loss to a point where, if they were people, they would benefit from a hearing aid. The researchers think that only a partial recovery was seen because the virus delivering the gene was not able to reach all the cells it needed to. There are two types of sound-sensing hair cells in the ear - inner hair cells that activate the auditory nerves carrying sound signals to the brain, and outer hair cells that amplify sound vibrations allowing people to hear really quiet sounds. TMC1 is needed by both cell types, but the virus was only able to get into and rescue the inner hair cells.

At least half of all childhood deafness is inherited and we know there are more than 100 different genes that can cause deafness. If shown to work in people, then this gene therapy has the potential to cure one specific type of genetic deafness (TMC1-related deafness). TMC1 accounts for around 6% of genetic deafness so, if this approach is successful, it will only have a direct benefit for a small number of families. However, more people could benefit in the future as the same technology could be adapted to treat other types of inherited deafness just delivering a healthy copy of a different gene. The only problem is that many forms of inherited deafness affect the ear before birth so in these cases, a childs ear would need to be treated during pregnancy which, with the technology and surgical techniques available today, would be very difficult. So for now, gene therapy to replace faulty genes is likely to be limited to treating progressive forms of inherited deafness that start after birth.

At the moment, this gene therapy is not yet ready to be tested in people. More work still needs to be done in the laboratory to refine the techniques, improve the way the virus delivers the healthy gene, understand how long the effect lasts for, and gather enough data to deem the approach safe and effective. If all goes well, the researchers hope to begin clinical trials in people in 5 years.

This research was published in the journal Science Translational Medicine

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New gene therapy research to treat genetic deafness ...

Jobing Description

Who we are:

Calico is a research and development company whose mission is to harness advanced technologies to increase our understanding of the biology that controls lifespan. We will use that knowledge to devise interventions that enable people to lead longer and healthier lives. Executing on this mission will require an unprecedented level of interdisciplinary effort and a long-term focus for which funding is already in place.

Position description:

Calico is recruiting biologists to work as part of a cutting-edge research team focused on studying and experimentally altering age-related physiological dysfunction in preclinical models. We are particularly excited about candidates with experience in gene therapy, vector-based delivery of genetic material in vivo, cell-based therapeutic strategies, and physiological endpoints in preclinical models. Experience with genome-editing technologies and pluripotent cell culture is a plus. The successful candidate will develop gene therapy tools to regulate biological networks in a temporal and tissue-specific manner, and to use those tools to alter age-related physiological dysfunction in a manner relevant to future clinical therapy.

Position requirements:

A Ph.D. in biology, cell biology, molecular biology, genetics, or biochemistry with a completed postdoc or 3+ years of additional, relevant experience, with a strong track record of research productivity as evidenced by high-quality, impactful publications. You need to be an enthusiastic team player, thrive on attention to detail, have excellent verbal/written communication skills, and be excited about studying aging!

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Research Specialist, Gene Therapy Job

ACGT is the only public charity in the nation exclusively funding cancer cell and gene therapy research. By supporting research in discovery and translational research, we stimulate both innovation and progress.

2014 Young Investigator Award, Posted: August 27, 2014 Abstract Deadline: September 16, 2014 at 4 pm E.S.T. Invitation to Submit Application: October 10, 2014 Deadline for Completed Application: November 6, 2014at1 pm E.S.T.

View the RFA (pdf) here.

All applications are to be uploaded atAltum Proposal Central.

The Investigators Award in Clinical Translation of Gene Therapy for Cancer distributes funds over 3-5 years, inclusive of a maximum of 10% indirect costs. Funds may be used at the recipients discretion for salary, technical assistance, supplies, animals or capital equipment, but may not support staff not directly related to the project, e.g. secretaries or administrative assistants. Purchase of equipment is not allowed in the final year of the grant.

A number of cell and gene therapy approaches for cancer have been shown to be efficacious and safe in laboratory animal models in the recent years, but their translation into clinical trials has been hindered by a lack of resources. Recognizing this critical need, ACGT is accepting grant applications to produce and release-testing of the clinical trial agents under cGMP, conduct the necessary pre-clinical pharmacological and toxicological studies in appropriate animal models, and/or conducting the clinical translational trials in patients in support of an Investigative New Drug (IND) application to the FDA. While the unambiguous demonstration of preclinical efficacy in cancer treatment by cell and gene therapy is a pre-requisite, entering into the clinical trial during the funding period is also a requirement. Applications that do not include this specific aim will be deemed unresponsive to the RFA.

Candidates must hold an MD, PhD, or equivalent degree and be a tenure-track or tenured faculty. The investigator must be conducting original research as an independent faculty member. ACGT has no citizenship restrictions; however, research supported by the award must be conducted at medical schools and research centers in the United States and Canada. Entering into clinical translation during the funding period is a requirement. Continued support is contingent upon submission and approval of a non-competitive renewal application each year.

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Research Grants for Cancer Cell & Gene Therapy | ACGT ...

The Technique Points to Safer, Simpler Potential HIV Treatment

LA JOLLA, CA July 1, 2012 Scientists at The Scripps Research Institute have discovered a surprisingly simple and safe method to disrupt specific genes within cells. The scientists highlighted the medical potential of the new technique by demonstrating its use as a safer alternative to an experimental gene therapy against HIV infection.

We showed that we can modify the genomes of cells without the troubles that have long been linked to traditional gene therapy techniques, said the studys senior author Carlos F. Barbas III, who is the Janet and Keith Kellogg II Professor of Molecular Biology and Chemistry at The Scripps Research Institute.

The new technique, reported in Nature Methods on July 1, 2012, employs zinc finger nuclease (ZFN) proteins, which can bind and cut DNA at precisely defined locations in the genome. ZFNs are coming into widespread use in scientific experiments and potential disease treatments, but typically are delivered into cells using potentially risky gene therapy methods.

The Scripps Research scientists simply added ZFN proteins directly to cells in a lab dish and found that the proteins crossed into the cells and performed their gene-cutting functions with high efficiency and minimal collateral damage.

This work removes a major bottleneck in the efficient use of ZFN proteins as a gene therapy tool in humans, said Michael K. Reddy, who oversees transcription mechanism grants at the National Institutes of Healths (NIH) National Institute of General Medical Sciences, which helped fund the work, along with an NIH Directors Pioneer Award. "The directness of Dr. Barbas's approach of simply testing the notion that ZFNs could possess an intrinsic cell-penetrating ability is a testament to his highly creative nature and further validates his selection as a 2010 recipient of an NIH Directors Pioneer Award.

Questioning Assumptions

ZFNs, invented in the mid-1990s, are artificial constructs made of two types of protein: a zinc-finger structure that can be designed to bind to a specific short DNA sequence, and a nuclease enzyme that will cut DNA at that binding site in a way that cells cant repair easily. The original technology to make designer zinc finger proteins that are used to direct nucleases to their target genes was first invented by Barbas in the early 1990s.

Scientists had assumed that ZFN proteins cannot cross cell membranes, so the standard ZFN delivery method has been a gene-therapy technique employing a relatively harmless virus to carry a designer ZFN gene into cells. Once inside, the ZFN gene starts producing ZFN proteins, which seek and destroy their target gene within the cellular DNA.

One risk of the gene-therapy approach is that viral DNAeven if the virus is not a retrovirusmay end up being incorporated randomly into cellular DNA, disrupting a valuable gene such as a tumor-suppressor gene. Another risk with this delivery method is that ZFN genes will end up producing too many ZFN proteins, resulting in a high number of off-target DNA cuts. The viral delivery approach involves a lot of off-target damage, said Barbas.

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Scripps Research Institute Scientists Develop Alternative ...

Media Contact: Monica Coenraads Executive Director, RSRT monica@rsrt.org203.445.0041

August 20, 2013

[Spanish Translation] [German Translation]

The concept behind gene therapy is simple: deliver a healthy gene to compensate for one that is mutated. New research published today in the Journal of Neuroscience suggests this approach may eventually be a feasible option to treat Rett Syndrome, the most disabling of the autism spectrum disorders. Gail Mandel, Ph.D., a Howard Hughes Investigator at Oregon Health and Sciences University, led the study. The Rett Syndrome Research Trust, with generous support from the Rett Syndrome Research Trust UK and Rett Syndrome Research & Treatment Foundation, funded this work through the MECP2 Consortium.

In 2007, co-author Adrian Bird, Ph.D., at the University of Edinburgh astonished the scientific community with proof-of-concept that Rett is curable, by reversing symptoms in adult mice. His unexpected results catalyzed labs around the world to pursue a multitude of strategies to extend the pre-clinical findings to people.

Todays study is the first to show reversal of symptoms in fully symptomatic mice using techniques of gene therapy that have potential for clinical application.

Rett Syndrome is an X-linked neurological disorder primarily affecting girls; in the US, about 1 in 10,000 children a year are born with Rett. In most cases symptoms begin to manifest between 6 and 18 months of age, as developmental milestones are missed or lost. The regression that follows is characterized by loss of speech, mobility, and functional hand use, which is often replaced by Retts signature gesture: hand-wringing, sometimes so intense that it is a constant during every waking hour. Other symptoms include seizures, tremors, orthopedic and digestive problems, disordered breathing and other autonomic impairments, sensory issues and anxiety. Most children live into adulthood and require round-the-clock care.

The cause of Rett Syndromes terrible constellation of symptoms lies in mutations of anX-linked gene called MECP2 (methyl CpG-binding protein). MECP2 is a master gene that regulates the activity of many other genes, switching them on or off.

Gene therapy is well suited for this disorder, Dr. Mandel explains. Because MECP2 binds to DNA throughout the genome, there is no single gene currently that we can point to and target with a drug. Therefore the best chance of having a major impact on the disorder is to correct the underlying defect in as many cells throughout the body as possible. Gene therapy allows us to do that.

Healthy genes can be delivered into cells aboard a virus, which acts as a Trojan horse. Many different types of these Trojan horses exist. Dr. Mandel used adeno-associated virus serotype 9 (AAV9), which has the unusual and attractive ability to cross the blood-brain barrier. This allows the virus and its cargo to be administered intravenously, instead of employing more invasive direct brain delivery systems that require drilling burr holes into the skull.

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Research update: First pre-clinical gene therapy study to ...

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Newswise Florida Atlantic University, one of Floridas leading public research universities, and the internationally renowned Nansen Neuroscience Network (NNN) in Norway, a premier network of organizations dedicated to research into neuroscience in Europe, have signed a memorandum of understanding for cooperative research and education in the areas of neuroscience and brain health.

Neuroscience research holds the key to some of the greatest challenges for our healthcare systems and societies in the decades to come, said Bjarte Reve, CEO of NNN. We believe that partnerships across countries and disciplines will be vital in addressing these challenges, and we are therefore delighted that our bonds to Florida Atlantic University and their impressive network in brain health and neuroscience are now being strengthened.

Neuroscience is a strategic research and education focus at FAU, and this new collaboration will expand upon the Universitys existing relationships with other leading scientific institutions such as Max Planck Florida Institute for Neuroscience, Scripps Florida, Torrey Pines Institute for Molecular Studies, and Vaccine and Gene Therapy Institute. In early March, FAU, Max Planck and Scripps unveiled plans to transform FAUs John D. MacArthur Campus in Jupiter into a neuroscience and life science hub in Florida.

We are extremely proud to partner with Nansen Neuroscience Network to further our research and education programs in the neurosciences, said FAU President John Kelly. Many of the top neuroscience institutions in Scandinavia, including members from Kavli Institute for Systems Neuroscience who were recently awarded the Nobel Prize in Medicine for their work in identifying the brains GPS system, are members of the Nansen Neuroscience Network. We are excited to join this prestigious organization to help address the many complex issues of brain health that impact us across the globe.

As part of the cooperative agreement, FAU and NNN plan to share specialized scientific equipment, physical facilities and support services in ways that will expand and provide more cost effective research and education for both organizations. In addition, FAUs Jupiter campus is home to both Max Planck Florida and Scripps Florida. A state-of-the-art electron microscope that is housed at Max Planck Florida is found in only a handful of places in North America and provides a unique glimpse of the brains wiring. It is the only microscope in North America capable of creating a 3D map of the brains neurons.

Neuroscience is one of the fastest developing areas of medical research and requires a multi-pronged approach through the integration of different sub disciplines, spanning from gene regulation and synaptic biology to neural systems, bioinformatics, biobanks, medical imaging, psychiatry and studies of behavior.

NNN is devoted to basic and applied research in neuroscience, including brain imaging, neurological and neuropsychiatric diseases, dementia and normal brain aging. The organizations aim is to expand the network into a comprehensive national endeavour working with patient support groups, strategic initiatives, the clinical community and industry, and from this broad network build a strong and internationally recognized innovation cluster.

FAU is home to the Center for Complex Systems and Brain Sciences and has three Ph.D. programs in neuroscience. In 2012, FAU and Max Planck initiated a joint graduate program in Integrative Biology and Neuroscience (IBAN), a strong research and academic partnership utilizing faculty from both institutions. In addition, researchers at FAU are investigating various neurodegenerative diseases such as Alzheimers and Parkinsons disease as well as addiction, epilepsy, stroke, and mental illness as a risk factor for obesity, diabetes and death.

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Florida Atlantic University Signs Collaboration Agreement with Internationally Renowned Nansen Neuroscience Network in ...

Posted: Monday, April 13, 2015 8:31 am

Evans to discuss gene therapy at Mayo , Post-Bulletin staff Post-Bulletin Company, LLC

Christopher H. Evans, Ph.D., will speak about gene therapy at the Sigma Xi Public Lecture at 7:30 p.m. on April 21 in Phillips Hall at the Mayo Clinic.

Evans is professor and director of the Rehabilitation Medicine Research Center at Mayo Clinic, and he's the Maurice Muller Professor of Orthopaedic Surgery Emeritus at Harvard Medical School.

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Newswise PHILADELPHIA The laboratory of David Weiner, PhD, a professor of Pathology and Laboratory Medicine at the Perelman School of Medicine at the University of Pennsylvania, received the 2015 Vaccine Industry Excellence Award for Best Academic Research Team, at the World Vaccine Congress in Washington, DC this week. The Congress is an annual meeting of vaccine professionals from industry, academia, and non-profit organizations.

It is a great honor to receive this important award, especially with such an exceptional field of deserving finalists, says Weiner. This award is testimony to the many wonderful scientists who I have been lucky to have had pass through my laboratory, as well as those that I have been fortunate to collaborate with from academia or industry, and to the exceptional research environment present at Penn.

The Weiner lab's DNA vaccines program was chosen over other finalists from Duke University, Harvard Medical School, and the Memorial Sloan-Kettering Cancer Center by hundreds of vaccine stakeholders who voted for those most deserving of recognition for their work across 14 vaccine-related categories.

This award, given annually to the research group that has produced products with a novel mode of action, seen them progress into human trials, and can demonstrate significant supportive research grants, was given to Weiner and his lab for making significant contributions to the field of DNA vaccines.

Weiner is also chair of the Gene Therapy and Vaccine Program and co-leader of Tumor Virology Program in the Abramson Cancer Center.

###

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $4.9 billion enterprise.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 17 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $409 million awarded in the 2014 fiscal year.

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Research Team from Penn Receives Vaccine Industry Excellence Award

Researchers of the Nanobiology Unit from the UAB Institute of Biotechnology and Biomedicine, led by Antonio Villaverde, managed to create artificial viruses, protein complexes with the ability of self-assembling and forming nanoparticles which are capable of surrounding DNA fragments, penetrating the cells and reaching the nucleus in a very efficient manner, where they then release the therapeutic DNA fragments. The achievement represents an alternative with no biological risk to the use of viruses in gene therapy.

Gene therapy, which is the insertion of genes into the genome with therapeutic aims, needs elements which can transfer these genes to the nucleus of the cells. One of the possibilities when transferring these genes is the use of a virus, although this is not exempt of risks. That is why scientists strive to find an alternative. With this as their objective, emerging nanomedicines aim to imitate viral activities in the form of adjustable nanoparticles which can release nucleic acids and other drugs into the target cell.

Among the great diversity of materials tested by researchers, proteins are biocompatible, biodegradable and offer a large variety of functions which can be adjusted and used in genetic engineering. Nevertheless, it is very complicated to control the way in which protein blocks are organised, in order to form more complex structures which could be used to transport DNA in an efficient manner, as happens with viruses.

Professor Antonio Villaverde's group has discovered the combination necessary to make these proteins act as an artificial virus and self-assemble themselves to form regular protein nanoparticles capable of penetrating target cells and reaching the nucleus in a very efficient manner. In chemical terms, the key lies in a combination of cation-peptide and hexahistidine placed respectively at the amino and C-terminus ends of the modular proteins.

Researchers from the UAB have demonstrated that, when in the presence of DNA, these artificial viruses surround it and carry out structural readjustments so that the DNA is protected against external agents in a similar fashion to how natural viruses protect DNA inside a protein shell. Even the forms adopted by the resulting structures seem to imitate virus forms.

"It is important to highlight that this ability to self-assemble does not depend on the structural protein chosen and does not seem limited to one particular type of protein. This provides the opportunity to select proteins which could avoid any type of immune response after being administered, which is of great advantage in terms of therapeutic uses", Villaverde points out.

"These artificial viruses are promising alternatives to natural protein nanoparticles, including viruses, given that their limitations, such as a rigid architecture and a lack in biosecurity, can be less adequate when used in nanomedicine", states Esther Vzquez, co-author of the study and responsible for the Clinical Nanobiotechnology research line within the Nanobiotechnology Unit of the UAB Institute of Biotechnology and Biomedicine (IBB).

What occurs in chemotherapy as a cancer treatment can also be compared to the problems in gene therapy. Conventional treatments have an extremely high toxicity which limits their applicability. For this reason, UAB researchers, in collaboration with Professor Ramon Mangues from Sant Pau Hospital and Professor Ramon Eritja from CSIC, are now adapting these artificial viruses to be able to transport anti-cancer drugs directly to tumour cells. In this way, they will be capable of releasing large therapeutic doses in a very localised manner.

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UAB researchers develop a harmless artificial virus for gene therapy

15 hours ago

Researchers of the Nanobiology Unit from the UAB Institute of Biotechnology and Biomedicine, led by Antonio Villaverde, managed to create artificial viruses, protein complexes with the ability of self-assembling and forming nanoparticles which are capable of surrounding DNA fragments, penetrating the cells and reaching the nucleus in a very efficient manner, where they then release the therapeutic DNA fragments. The achievement represents an alternative with no biological risk to the use of viruses in gene therapy.

Gene therapy, which is the insertion of genes into the genome with therapeutic aims, needs elements which can transfer these genes to the nucleus of the cells. One of the possibilities when transferring these genes is the use of a virus, although this is not exempt of risks. That is why scientists strive to find an alternative. With this as their objective, emerging nanomedicines aim to imitate viral activities in the form of adjustable nanoparticles which can release nucleic acids and other drugs into the target cell.

Among the great diversity of materials tested by researchers, proteins are biocompatible, biodegradable and offer a large variety of functions which can be adjusted and used in genetic engineering. Nevertheless, it is very complicated to control the way in which protein blocks are organised, in order to form more complex structures which could be used to transport DNA in an efficient manner, as happens with viruses.

Professor Antonio Villaverde's group has discovered the combination necessary to make these proteins act as an artificial virus and self-assemble themselves to form regular protein nanoparticles capable of penetrating target cells and reaching the nucleus in a very efficient manner. In chemical terms, the key lies in a combination of cation-peptide and hexahistidine placed respectively at the amino and C-terminus ends of the modular proteins.

Researchers from the UAB have demonstrated that, when in the presence of DNA, these artificial viruses surround it and carry out structural readjustments so that the DNA is protected against external agents in a similar fashion to how natural viruses protect DNA inside a protein shell. Even the forms adopted by the resulting structures seem to imitate virus forms.

"It is important to highlight that this ability to self-assemble does not depend on the structural protein chosen and does not seem limited to one particular type of protein. This provides the opportunity to select proteins which could avoid any type of immune response after being administered, which is of great advantage in terms of therapeutic uses", Villaverde points out.

"These artificial viruses are promising alternatives to natural protein nanoparticles, including viruses, given that their limitations, such as a rigid architecture and a lack in biosecurity, can be less adequate when used in nanomedicine", states Esther Vzquez, co-author of the study and responsible for the Clinical Nanobiotechnology research line within the Nanobiotechnology Unit of the UAB Institute of Biotechnology and Biomedicine (IBB).

What occurs in chemotherapy as a cancer treatment can also be compared to the problems in gene therapy. Conventional treatments have an extremely high toxicity which limits their applicability. For this reason, UAB researchers, in collaboration with Professor Ramon Mangues from Sant Pau Hospital and Professor Ramon Eritja from CSIC, are now adapting these artificial viruses to be able to transport anti-cancer drugs directly to tumour cells. In this way, they will be capable of releasing large therapeutic doses in a very localised manner.

Explore further: New protein booster may lead to better DNA vaccines and gene therapy

Read the original:
Researchers develop harmless artificial virus for gene therapy

By Dow Jones Business News, April 06, 2015, 08:36:00 AM EDT

By Angela Chen

Bristol-Myers Squibb Co. agreed to invest in the Dutch company UniQure NV and work together on gene therapies for cardiovascular disease.

Bristol-Myers will have exclusive access to the Dutch company's proprietary gene therapy program for congestive heart failure. The two companies will collaborate on 10 targets in total and may work on future projects in other disease areas.

Bristol-Myers will pay about $100 million. This includes an upfront payment of $50 million, a $15 million payment for selecting two collaboration targets, and a $32 investment in UniQure that represents a 4.9% stake in the company. Bristol-Myers will acquire an additional 5% ownership before the end of the year at a 10% premium.

UniQure can receive at least an additional $254 million if certain milestones are reached. It is also eligible for $217 million for other gene therapy products.

Shares of UniQure surged 42% in premarket trading to $32.45. Bristol-Myers shares, up 27% over the past year, slipped 0.4% to $63.

Amsterdam-based UniQure will make supplies using its insect-cell based manufacturing platform. Bristol-Myers will pay for research and development costs as well as lead development and commercialization.

"This collaboration will accelerate the application of gene therapy for large patient populations suffering from heart diseases and will complement the further development of UniQure's internal pipeline," UniQure Chief Executive Joern Aldag said.

New York-based Bristol-Myers is poised for a management shift, with Chief Operating Officer Giovanni Caforio set to become chief executive in May. Dr. Caforio, a trained physician, will succeed CEO Lamberto Andreotti, who will become chairman of the board.

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Bristol-Myers Invests in UniQure in Heart Disease Pact

Christopher Jewell, an assistant professor in the University of Maryland Fischell Department of Bioengineering, was awarded a three-year, $250,000 grant from the Alliance for Cancer Gene Therapy to develop gene therapy to promote cancer immunity, the university and the alliance announced Monday.

Jewell's research could create vaccine "depots" among the lymph nodes, specialized tissues that control responses against disease and infection.

The alliance is a nonprofit that sponsors promising research into cell and gene therapies to battle cancer. Jewell is one of two grant recipients this year and among 46 since 2001 from the alliance, which has a goal of replacing radiation, chemotherapy and surgery, while turning cancer into a manageable, treatable disease.

The Stamford, Conn.-based group has handed out more than $25 million in funding for the cause.

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Maryland researcher wins grant to study alternative cancer therapy

Stamford, CT (PRWEB) March 16, 2015

Alliance for Cancer Gene Therapy (ACGT) the nations only nonprofit dedicated exclusively to cell and gene therapies for cancer has achieved a major milestone, surpassing $25 million donated to innovative and breakthrough cancer research. ACGT was founded by Barbara Netter and her late husband, Edward, in 2001 with the goal of transforming cancer into a manageable, treatable disease.

Pushing the foundation across the $25 million threshold are a pair of three-year, $250,000 grants to two esteemed scientists: Meenakshi Hegde, MD, of Texas Childrens Cancer Center at Baylor College of Medicine in Houston, TX, and Christopher Jewell, PhD, at University of Maryland, College Park. Dr. Hegdes work will focus on immunotherapy, specifically adoptive cellular therapy for melanoma. Dr. Jewells research is centered on harnessing intra-lymph node gene therapy to promote tumor immunity. The grantees will develop genetically-modified T cells and cancer vaccines with the potential to stop cancer in its tracks.

Drs. Hegde and Jewell are two outstanding scientists in the vanguard of treating and defeating cancer, said Barbara Netter, ACGTs President. Their work offers tremendous hope to those battling cancer, and also to their loved ones.

ACGT grants are awarded to promising researchers whose work dovetails with the foundations mission: Leveraging cell and gene therapies to supplant the more harrowing cancer treatments like radiation, chemotherapy and surgery. ACGTs $25 million in grants have funded watershed research and trials such as those that activate patients own immune systems to battle cancer cells. These trials have saved the lives of cancer patients otherwise believed to be beyond treatment.

The two most recent grants continue ACGTs mission of equipping innovative scientists with the tools and support to revolutionize the fight against cancer. ACGT grants range from $250,000 to $1 million, and reward both young, promising researchers and their more established colleagues. Past recipients include such pre-eminent scientists as University of Pennsylvanias Dr. Carl June and Memorial Sloan-Ketterings Dr. Michel Sadelain; this past summer, the Food and Drug Administration (FDA) granted breakthrough status to immunotherapy treatments for leukemia developed by each of these scientists for which ACGT provided early funding.

About Alliance for Cancer Gene Therapy (ACGT) Established in 2001, ACGT (http://www.acgtfoundation.org) is the nations only not-for-profit dedicated exclusively to cell and gene therapy treatments for all types of cancer. One-hundred percent of contributions go directly to research. ACGT has funded 46 grants in the U.S. and Canada since its founding in 2001 by Barbara Netter, President, and her late husband, Edward, to conduct and accelerate critically needed innovative research. Since its inception, ACGT has awarded 31 grants to Young Investigators and 15 grants to Clinical Investigators, totaling more than $25 million in funding. ACGT is located at 96 Cummings Point Road, Stamford, CT 06902.

ACGT on Facebook: http://www.facebook.com/ACGTfoundation ACGT on Twitter: http://www.twitter.com/ACGTfoundation ACGT on YouTube: http://www.youtube.com/user/ACGTfoundation

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ACGT Surpasses $25 Million Funding Milestone with Two New Grants