ASGCT Press Release

Today's findings from the ASGT Annual Meeting: New research on non-malignant acquired disorders and gene therapy of cancer

Gene therapy of Amyotrophic Lateral Sclerosis (Lou Gehrig's disease) by in vivo electroporation in muscle
BOSTON (Thursday, June 6, 2002) -- Lou Gehrig's disease, a motor neuron disease, is a devastating and progressive affliction of the nerves that control muscles. Patients develop progressive weakness and eventually die, usually of respiratory failure. So far there has been no successful treatment for this disease. According to researchers at the American Society of Gene Therapy Annual Meeting, one possible approach to treatment is to inject genes that encode for growth factors for the nerves, such as Ciliary Neurotrophic Factor, Neurotrophin-3 and Cardiotrophin, which all work effectively in mice.

Jeanne-Claire Lesbordes of the Institut Cohin, Paris, France and colleagues, demonstrate that intramuscularly injected CT-1 plasmid allows after in vivo electroporation, to prolong survival and improve neurological symptoms in the pmn mice. Pmn mice are a model for Motor Neuron Disease, a SMA-like model, but they are not really a model for Amyotrophic Lateral Sclerosis (Lou Gehrig's disease).

Researchers concluded that these encouraging results might lead to the institution of clinical studies.

Possible AIDS Treatment
BOSTON (Thursday, June 6, 2002) -- Although highly active antiretroviral therapies have greatly prolonged the lifespan of patients with AIDS, this condition remains a lethal disorder and the adverse effects of chemotherapy are often disabling. According to researchers at the American Society of Gene Therapy Annual Meeting, the introduction of a genetic element to target cells, thereby inhibiting HIV replication and its pathogenic affect, may represent a novel treatment for HIV/AIDS.

Geoff Symonds, PhD, and colleagues conducted a 3-year Phase I study of 10 patients who were given hematopoietic stem cells that contained a ribozyme, that in vitro studies suggest is capable of splitting one of the crucial HIV genes (the tat gene), thereby rendering it inactive. Patients received cells containing this protective ribozyme vector and cells containing a marker vector.

Researchers found that no serious adverse events occurred and the transferred gene could be detected for the full 3 years of the study. There was longer survival of the ribozyme containing T-lymphocytes than the marker gene T cells. Researchers concluded that this approach merits further study as a means of repopulating patients with protected immune system cells.

Limiting coronary damage
BOSTON (Thursday, June 6, 2002) -- Cardiovascular disease is the leading cause of death in the United States, and it's important to be able to limit the damage caused to the heart following coronary artery blockage.

In research presented at the American Society of Gene Therapy Annual Meeting, Luis Melo, PhD, and colleagues from Brigham Young and Women's Hospital & Harvard Medical School, Boston, showed that the transfer of a gene normally expressed by cells under stress could protect the heart muscle cells from damage caused by blockage of their blood vessels. In a series of rat studies, they showed that expression of the gene hemeoxygenase reduced the short-and long-term damage to the heart after coronary artery blockage and improved the function of the organ.

Researchers concluded that this approach could be explored for treatment of human disease allowing protection of heart muscle after myocardial infarction and thereby limiting the damage caused.

New tumor treatment
BOSTON (Thursday, June 6, 2002) -- Many tumors express their surface unique structures or antigens that could be the target for an anti cancer immune response. Unfortunately, many of these tumors also express genes that inactivate this immune response. According to researchers at the American Society of Gene Therapy Annual Meeting, one of the most important of these gene codes for a protein is called transforming growth factor-beta (TGFb ).

Catherine Bollard, MD, and colleagues reported a way in which immune cells can be made to express a mutant receptor for TGFb , which makes them resistant to inactivation by this substance. Researchers found that cells that express this mutant TGFb receptor will effectively proliferate and kill tumor cell targets, even when the cancers express levels of TGFb that would usually be capable of switching off an immune response.

The first application of this approach will be in patients with Epstein-Barr virus positive Hodgkin disease, who will be treated with EBV specific TGFb resistant immune cells.

Activating the immune system
BOSTON (Thursday, June 6, 2002) -- Vaccination with DNA from another species is a well-recognized method for increasing the immune response for tumor antigens. According to researchers at the American Society of Gene Therapy Annual Meeting, by using a gene from a separate species, the immune system can sometimes be highly activated.

Jedd Wolchok, MD, PhD, and colleagues carried out a clinical trial in dogs who had a form of cancer called canine malignant melanoma (CMM), which is similar to advanced human melanoma. Nine dogs with advanced CMM were injected with a plasmid DNA containing the gene for human tyrosinase (an enzyme highly active in malignant melanoma). One dog had a complete response and three have stable disease or remain without evidence of disease. Five dogs failed to improve. Researchers concluded that the data strongly suggests that "xenogenic" DNA vaccination is safe and may prove to be an effective treatment for some types of cancer.

Developing new cancer treatment
BOSTON (Thursday, June 6, 2002) -- The first successful Phase II gene therapy clinical trial for the treatment of cancer in 2000 used an oncolytic (i.e., cancer killing) conditionally replicative adenovirus. This is an adenovirus that is able to multiply within the patient's body, but primarily in the cancer cells. According to researchers at the American Society of Gene Therapy Annual Meeting, the ongoing effort has been to develop more effective oncolytic vectors that would replicate solely in cancer cells and, therefore, would have a high margin of safety.

Jane Lebkowski, PhD, Geron Corporation, Menlo Park, CA, and colleagues created an adenovirus containing a critical viral gene called E1A, under the control of a human telomerase reverse transcriptase (hTERT) gene. Combined together, the telomerase promotor-driven oncolytic virus is engineered to selectively replicate in and kill targeted cancer cells expressing telomerase, leaving healthy normal tissues (that are telomerase negative) largely unharmed.

Researchers conducted tests using the telomerase promoter-oncolytic virus (ad2p/hTERT-E1A) in mice with pre-existing human liver and prostate cancer. At the end of the experiment, 80-90 percent of the mice treated showed significant tumor regression. In 43 percent of liver-cancer bearing mice tumors regressed completely and the mice remained tumor free for the full study duration. Additionally, 50 percent of prostate cancer bearing mice became tumor free and remained so over the test period. The surrounding normal cells remained unharmed and no toxic effects were observed in the treated mice.

The studies confirm how on oncolytic virus, when controlled by the telomerase promoter, can effectively kill a wide variety of human cancer cell types and therefore could be used to treat many types of cancer.

The American Society of Gene & Cell Therapy (ASGCT) is a professional non-profit medical and scientific organization dedicated to the understanding, development and application of genetic and cellular therapies and the promotion of professional and public education in the field. For more information on ASGCT, visit its website, www.asgct.org.

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