Genzyme gene therapy for people with peripheral artery disease failed in a clinical trial to help them regain some mobility

Score another one in the loss column for gene therapy. Cambridge, MA-based Genzyme said yesterday at a medical meeting that its gene therapy for people with peripheral artery disease failed in a clinical trial to help them regain some mobility.

The trial—one of the largest in the field of gene therapy—enrolled 289 patients who were injected with either a placebo or a low, medium, or high dose of Genzyme’s gene therapy treatment, researchers said at the American College of Cardiology meeting in Orlando, FL. The treatment, designed to deliver a copy of a gene called HIF1a, was supposed to help stimulate the growth of new blood vessels around clogged arteries in the legs, improving circulation and allowing people with severely limited mobility to walk for longer periods of time.

A New Zealand study found that a gene therapy helped obese mice reduce their body weight by 20% after three weeks of treatment. The therapy involved the injection of as many as three kinds of genetic material into their brains. Plans are under way to begin clinical trials to control obesity in humans.

Fatal brain cancer tamed by New gene therapy
Rats with an aggressive form of human brain cancer have been successfully treated with gene therapy that “trains” the immune system to attack tumours.

The results could pave the way for human trials early next year, say researchers who developed the system at the Cedars-Sinai Medical Center in Los Angeles.

Previous attempts to treat glioblastomas with gene therapy failed because some tumour cells survived and regrew. The new treatment overcomes this problem by permanently priming the immune system to pick off any straggler tumour cells.

A harmless virus that only infects fast-dividing cancer cells is injected directly into the brain, and used to deliver the therapeutic genes into the tumour. One gene, HSV1-TK, kills the cancer cells by activating ganciclovir, an otherwise ineffective drug administered into the rat’s abdomen. Yet the key to the therapy’s long-term success is a second gene, Flt3L, which summons immune “dendritic” cells from the bloodstream into the brain.

These cells engulf the debris and transport it back to lymph nodes, where they re-prime the immune system to attack any remaining tumour cells during and after treatment. The work will appear in Molecular Therapy
For more details
http://www.newscientist.com/article/mg19726444.900-fatal-brain-cancer-tamed-by-gene-therapy.html

Researchers Identify Gene for Rare Form of Spinal Muscular Atrophy
TUCSON, Ariz. — Flaws in a gene known as UBE1 have been identified as the cause of a rare, X-chromosome-linked form of spinal muscular atrophy (SMA), a severe neurodegenerative disease, the Muscular Dystrophy Association (MDA) announced today.

Lisa Baumbach-Reardon, an associate research professor and head of the Neurogenetics Laboratory at the University of Miami (Fla.), who received MDA support for this work, led the study team with Alfons Meindl at Technical University Munich (Germany). The researchers published their findings in today’s issue of the American Journal of Human Genetics.

Having a second gene identified that causes symptoms of SMA is extremely important, not only for the development of better diagnostic tests but also for the development of new animal models and new therapeutic approaches,” said Sharon Hesterlee, MDA vice president for translational research.

The vast majority of SMA cases are caused by a mutation in the SMN1 gene on chromosome 5, which was identified in the mid-1990s. The chromosome-5 form of the disease affects both sexes and ranges in severity from the very severe and often-fatal infantile-onset form (type 1) to the somewhat less severe forms, type 2 and type 3.

The X-chromosome form of the disease, which affects male babies, occurs in a small percentage of SMA cases. Its exact incidence is unknown.

The disease closely resembles the type 1, chromosome-5 form of SMA in all respects except that it also affects the joints, which are not affected in chromosome-5 SMA.

The X-linked disease, which is present at birth, results in low muscle tone, absent reflexes, and multiple contractures (frozen joints) in association with loss of muscle-controlling nerve cells (motor neurons) in the spinal cord. It leads to death within two years.

The underlying genetic cause is any of a number of abnormalities (mutations) in a gene on the X chromosome that carries instructions for “ubiquitin-activating enzyme E1” (UBE1). This enzyme’s normal job in cells is to help attach ubiquitin molecules to proteins the cell needs to destroy. The ubiquitin “tag” marks proteins for destruction. Altered function of this protein disposal system is the likely mechanism by which X-linked SMA occurs.

The investigators screened four North American, one Mexican and one Thai family in which X-linked SMA was suspected and compared their X chromosomes to X chromosomes from unaffected people.

They screened 3,550 chromosomes from unaffected people for two of the UBE1 mutations suspected of causing X-linked SMA and found no instances of either mutation. A third suspected mutation in the same gene was not found in 7,914 chromosomes from people without the disease.

“This study is the culmination of 15 years of investigation, starting with identification of the first families with X-linked SMA, through years of gene-mapping studies to finally, last year, gene discovery and mutation identification.

“It’s been a long road, but we never gave up, because we promised the families who have this devastating illness that, with their participation in our research studies, we would someday identify the causal disease gene,” Baumbach-Reardon said. “Along the way, we’ve worked with an international team of geneticists, genetic counselors and scientists. We all share in the excitement and the hope that this discovery brings.”

About MDA

MDA is a voluntary health agency working to defeat more than 40 neuromuscular diseases, including SMA, through programs of worldwide research, comprehensive services, and far-reaching professional and public health education. For more information, visit http://www.mda.org.

Dystrophin Gene Transfer safe in Duchenne muscular dystrophy
An Muscular Dystrophy Association supported trial to transfer genes for the muscle protein dystrophin, needed but missing in Duchenne muscular dystrophy (DMD), has shown that the procedure is safe and well tolerated in six boys. Researchers plan to test three additional patients at a higher dosage level.

In this trial, which began in March 2006, researchers injected a dystrophin gene compound called Biostrophin, which was developed with MDA support at Asklepios Biopharmaceutical in Chapel Hill, N.C., into the biceps muscles of boys with DMD.
Biostrophin is a combination of miniaturized dystrophin genes and adeno-associated viral shells that home to muscle fibers.

“The patients have been injected with the gene carried by an adeno-associated virus into one muscle of the arm,” said neurologist Jerry Mendell, director of the Gene Therapy Center and the clinician on the study. He also serves as co-director of the MDA clinics at Nationwide Children’s and Ohio State University Hospitals in Columbus. Mendell injected the children at Nationwide Children’s Hospital.

“The patients have been carefully followed for side effects of the treatment, and none have been encountered,” he said. “This is primarily a safety trial, and we can confidently report that safety has been achieved. An additional goal is to lay the ground work for future gene therapy trials by establishing the ideal dose for treatment. In this trial, two doses have been tested, and another will be required before completion of the study.” Mendell said the three additional trial participants will “receive a higher dose, which by all indications will be safe to administer.” {No participants are being recruited at this time.}

“Upon completion of the trial in nine subjects, we will be able to report to the scientific community and the public the results of the trial,” he said, “with recommendations for future gene therapy trials for this devastating form of muscular dystrophy.”

Isis Enters Broad Collaboration With Ortho-McNeil, Inc. for the Discovery, Development and Commercialization of Antisense Drugs to Treat Metabolic Diseases
- Includes license of two antisense drugs in development targeting glucagon receptor and glucocorticoid receptor – Includes research collaboration to identify antisense drugs to inhibit additional targets to treat metabolic diseases.

Isis Pharmaceuticals, Inc. (Nasdaq: ISIS) today announced a broad collaboration with Ortho-McNeil, Inc., a Johnson & Johnson
company, to discover, develop and commercialize antisense drugs to treat metabolic diseases, including Type 2 diabetes. As
part of the collaboration, Isis will grant to Ortho-McNeil worldwide development and commercialization rights to two of its
diabetes development candidates, ISIS 325568 and ISIS 377131, which selectively inhibit the production of glucagon receptor
(GCGR) and glucocorticoid receptor (GCCR), respectively. Additionally, Ortho-McNeil will provide funding to Isis to support the joint discovery of novel drugs to treat metabolic diseases, including diabetes and obesity. After the initial collaboration phase,
Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (J&JPRD) will continue development of these drugs.
Ortho-McNeil will pay Isis a $45 million upfront licensing fee, and will provide Isis with research and development funding over
the period of the collaboration. In addition to the licensing fee, Isis could receive over $230 million in milestone payments upon
successful development and regulatory approvals of ISIS 325568 and ISIS 377131, as well as royalties on sales. Isis could also
receive milestones and royalties on the successful development and regulatory approvals of additional drugs discovered as
part of the collaboration. The agreement is subject to clearance under the Hart-Scott-Rodino Antitrust Improvements Act. Prior
to closing of the transaction, Isis plans to purchase the equity in Symphony GenIsis, Inc. and reacquire the intellectual property
related to the GCGR and GCCR programs as well as regain full ownership of ISIS 301012, the Company’s lipid-lowering drug
targeting Apolipoprotein B-100.
“We look forward to working with Ortho-McNeil, Inc. and J&JPRD to advance our glucagon receptor and glucocorticoid receptor
drugs through the clinic and to develop additional drugs against other promising targets,” said Lynne Parshall, J.D., Executive
Vice President and Chief Financial Officer, Isis pharmaceuticals. “This collaboration represents another major step for us in capturing value from our achievements in creating a new drug discovery platform technology and discovering commercially attractive antisense drugs.”
“This collaboration has been enabled by the productivity of our metabolic drug discovery program, which has evaluated more
than 120 targets in animal models using antisense drugs,” said Jeffrey Jonas, M.D., Executive Vice President, Isis
Pharmaceuticals. “Both ISIS 325568 and ISIS 377131 have broad and exciting therapeutic profiles that include lowering of
blood lipids and body fat, in addition to significant glucose-lowering effects. These drugs have demonstrated robust effects in extremely diabetic and hyperlipidemic animals and have demonstrated a unique and preferential distribution to tissues such as liver and fat, thereby potentially minimizing the systemic side effects that would be expected with traditional approaches against the same gene targets. We are enthusiastic about our research collaboration, which should allow us to discover additional
drugs against novel targets, thereby adding to our strong pipeline in this therapeutic area.”
About glucagon receptor (GCGR), target of ISIS 325568
Glucagon is a hormone that opposes the action of insulin and stimulates the liver to produce glucose. In Type 2 diabetes,
unopposed action of glucagon can lead to increased blood glucose levels. Reducing the expression of liver GCGR using
antisense inhibitors, and thereby reducing excessive liver glucose production, is expected to lower blood glucose levels and
help control Type 2 diabetes. In preclinical studies, antisense inhibitors of GCGR led to improved glucose control and reduced
levels of blood triglycerides without producing hypoglycemia.In addition, treatment with ISIS 325568 led to an increase in
circulating glucagon-like peptide, or GLP-1, which is a hormone that helps to preserve pancreatic function, thereby enhancing
insulin secretion.

About glucocorticoid receptor (GCCR), target of ISIS 377131
Glucocorticoid hormones have a variety of effects throughout the body, including promoting liver glucose production and fat
storage. Although inhibition of GCCR has long been recognized as an attractive strategy for development of therapeutics for
Type 2 diabetes, the side effects associated with systemic GCCR inhibition have challenged development of traditional drugs.
Antisense inhibitors of GCCR take advantage of the unique tissue distribution of oligonucleotides that allows the antisense
drugs to antagonize glucocortocoid action primarily in liver and fat tissue. Notably, antisense drugs do not reduce GCCR
expression in the central nervous system or adrenal glands — inhibition of GCCR expression in these two organs can lead to
systemic side effects. In preclinical studies, Isis has shown that ISIS 377131 has a broad therapeutic profile that includes
reduction of blood glucose levels, a dramatic and favorable effect on lipid levels including cholesterol and triglycerides, and a
reduction in body fat.

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The Gene Therapy Review Signs Deal with EBSCO Publishing

The Gene Therapy Review announces its new partnership with EBSCOhost, an agreement that will see its content distributed worldwide in a multitude of libraries. Articles submitted to the Gene Therapy Review will now also be directly available in school, college, university, hospital, governmental, corporate and public libraries. EBSCOhost is part of the EBSCO publishing group and functions by providing customers with an integrated service that combines reference databases, subscription management, online journals, books, linking services and A-to-Z solutions. Inclusion in the databases maintained and distributed by EBSCOhost should widen the exposure of the Gene Therapy Review and encourage new and exsiting users to submit new content and help build the most comprehensive source of gene therapy information on the web.

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If you are an active scientific researcher in the gene therapy arena, we would like to invite you to contribute to this new open resource. It is our aim to build a content-rich site that can be browsed by anyone wanting to expand their understanding of the development and application of novel genetic therapeutics. We ask you to submit a short description of the work that you and your laboratory currently undertake in gene therapy. This will then be listed in the relevant research directory that constitutes part of the site. Alternatively, if you are a clinician or patient currently invovlved in a gene therapy trial we are interested to hear your experiences or suggestions.

The Gene Therapy Review was founded in 2008 with a view to establishing the most comprehensive gene therapy resource on the web, with content provided by the gene therapy community. Registration is free and allows users complete access to all sections of the site. The Gene Therapy Review journal comprises all the articles written by our contributers and is published twice a year and is edited by Dr Michael L. Roberts who has more than 15 years experience developing various gene transfer vector systems. Moreover, a print edition featuring all the articles contributed to the Gene Therapy Review on a biannual basis is avaible at Amazon.com; to purchase the print copy follow this link.