Today's findings from the ASGT Annual Meeting:
New research on neurological disorders and cancer gene therapy

Model sheds new light on Huntington's Disease

SEATTLE (Friday, June 1, 2001) -- Gene transfer technology is most often associated with fixing a genetic problem or adding additional genetic functions for therapeutic reasons. According to researchers at the American Society of Gene Therapy Annual Meeting, the same technology can also be used to understand the genetic problems underlying a known human disease such as Huntington's disease (HD), a genetic neurodegenerative disease that mainly affects the striatum.

Nicole Deglon of the Division of Surgical Research and Gene Therapy Center in Lausanne, Switzerland, and colleagues developed a rat model of Huntington's disease. Researchers injected altered forms of Huntington's disease into rat brains to determine which mutations are associate with specific pathological results.

There is still no cure of effective treatment for Huntington's disease, however the results of these studies will not only shed light on critical genetic underpinnings of the disease, but may help develop lentiviral gene therapy vectors to correct it.

Lentiviral vectors could fix the behavior as well as the nerves

SEATTLE (Friday, June 1, 2001) -- Gene therapy research has often been stymied by procedures that appear to fix the appearance of damaged tissue but which do not repair its function. According to Antonella Consiglio of the Telethon Institute for Gene Therapy in Milano, Italy and colleagues at the American Society of Gene Therapy Annual Meeting, the use of lentiviral vectors to replace defective genes could be not only a structural but also a functional fix.

"Lysosomal storage disorders" are a group of phenotypically similar but genetically distinct diseases characterized by defects in genes encoding enzymes important to basic cellular metabolism. One of these, metachromatic leukodystrophy (MLD), results from a defect in the gene encoding the lysomal enzyme arylsulfatase A (ARSA), which results in myelin degeneration in both the central and peripheral nervous system. Lentivirus-mediated transfer of a normal ARSA gene into the brains of MLD animals has been shown to prevent the degeneration seen in the disease.

Researchers tested whether or not the animals were protected from the behavioral and functional sequelae of the disease by injecting young model mice, i.e, prior to the development of the disease, and then looked for deterioration of learning ability. They found that one injection of the lentiviral-ARSA vector was sufficient to prevent the onset of the disease. Upon subsequent histological analysis, both at the site of injection and throughout the other parts of the brain, researchers concluded the brains of these mice appeared largely normal.

How the preventive effects are spread throughout the brain from the single injection site remain unclear. There is evidence that it could be through cell-to-cell contact via neural projections or through infection by the gene therapy vector of neural precursor or stem cells at the site of injection, which then migrate to the other areas of the brain. This is particularly important to determine, as it will be necessary to harness this ability for treatment of relatively larger brained animals such as humans.

New approaches to cancer gene therapy alert immune system to presence and locations of tumors

SEATTLE (Friday, June 1, 2001) -- One hallmark of many cancers is that they successfully evade the usual immune system surveillance mechanisms that could keep them in check. Thus, many gene therapy approaches to cancer are trying to overcome this "hidden" status of tumors by having them express genes that alert the immune system to their presence and location. Two such approaches currently in clinical trials, one for melanoma patients and the other in renal cell carcinoma patients, were reviewed today at the American Society of Gene Therapy Annual Meeting.

In the first trial, Evan M. Hersh of the Arizona Cancer Center and colleagues from Vical, Inc. injected metastatic tumors directly with a plasmid DNA/lipid complex called "Allovectin-7," which carries the gene for a rare human immune molecule (HLA-B7) on the plasmid. Tumor cells take up the DNA/lipid complex and express pieces of the HLA-B7 protein on their surface, which is then recognized by the immune system as foreign, resulting ultimately in the destruction of the tumor cell. In addition, the immune system may then be primed to recognize other metastatic nodules. Allovectin-7 has been tested in both Phase I and Phase II clinical trials, and has been shown to be well-tolerated, and appears to have some efficacy, particularly in patients in whom the disease has not yet spread to the viscera.

The second trial tested an approach aimed at providing genes to tumor cells that encode immune stimulatory molecules. Researchers injected "Leuvectin," a plasmid DNA/lipid complex that carries the gene for interleukin-2 (IL-2), a potent immunostimulatory cytokine, directly into tumors of patients with metastatic renal cell carcinoma. Although IL-2 is used systemically for treating some cancers, such as metastatic renal cell cancer, this use has significant toxicity associated with it: local delivery of IL-2 by having the tumor cells make the protein themselves may overcome this problem. Researchers found that the Leuvectin treatment was well-tolerated and it had significant biological activity.

Both drugs are being further evaluated in planned large Phase II and Phase III trials.

New vaccine shows encouraging signs in combating non-small cell lung cancer

SEATTLE (Friday, June 1, 2001) -- A new vaccine shows encouraging signs of helping the body to recognize and destroy new or existing cancers in some patients suffering from advanced non-small cell lung cancer (NSCLC) according to a study released today at the American Society of Gene Therapy Annual Meeting.

Kristen Hege, of Cell Genesys, Inc., Foster City, CA and colleagues from across the country conducted a multi-center Phase I/II clinical trial of 80 patients suffering from advanced non-small cell lung cancer (NSCLC). Isolated tumor cells were treated with adenovirus containing the gene for granulocyte-macrophage colony stimulating factor (GM-CSF), a hormone which plays a key role in stimulating the body's immune response to vaccines. A whole-cell cancer vaccine composed of irradiated tumor cells that have been genetically modified to secrete GM-CSF, was administered under the skin of patients.

Researchers found good preliminary evidence of immunologic and clinical anti-tumor activity, leading them to conclude that this approach could work for at least some NSCLC patients.

The American Society of Gene Therapy is the largest medical professional organization representing researchers and scientists dedicated to discovering new gene therapies. ASGT was established in 1996, and has grown to more than 3,000 members. It is committed to promoting and fostering the general field of research involving gene therapy and to promoting professional and public education in all areas of gene therapy.

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