ASGT Press Release 

Promising research using gene therapy presented at ASGT 8th Annual Meeting in St. Louis

Researchers develop potential treatment for muscular dystrophy

ST. LOUIS - A study reporting the potential use of gene therapy for muscular dystrophy was presented today at the 8th Annual Meeting of the American Society of Gene Therapy (ASGT) in St. Louis.

Muscular dystrophy is caused by mutations in the dystrophin gene. In the absence of dystrophin, muscle cells die and ultimately become too weak for patients to breathe. It's not possible to deliver normal dystrophin genes to the muscle because it is extremely large for any gene transfer method and the delivery to the majority of the muscle cells would require trillions of virus particles.

However, in mild forms of the disease, the muscle cells are still able to produce almost normal dystrophin by "skipping" over the part of the gene containing the mutation, creating a smaller dystrophin protein. Using gene therapy techniques, French researchers have developed a way to encourage muscles to generate this effect. They discovered that a small RNA named U7 could promote the joining of blocks surrounding the mutation in the dytrophin gene of mice, causing it to be excluded, creating an RNA that generates almost normal protein.

Using adeno associated viruses vectors, researchers injected the U7 into the leg muscles of mice with muscular dystrophy. The mice were able to produce higher levels of dystrophin and the treated muscles contracted normally in response to exercise and other stimuli. The researchers concluded that a similar strategy could potentially be used on human patients in the future.

Researchers develop animal model to study leukemia caused by XSCID

A study reporting the first animal model system to study leukemia caused by gene therapy vectors was presented at the 8th Annual Meeting of the American Society of Gene Therapy in St. Louis.

Yah Shou, PhD, and colleagues, from St. Jude Children's Research hospital, Memphis, generated mice that had XSCID, and who were also predisposed to cancer. Gene therapy was successful in curing the mice of XSCID, just like it did in the human patients. However, similar to the three human patients, the mice developed T-cell leukemia at a significantly increased rate.

Through this model, researchers found that gene therapy vectors are often inserted into normal genes that can cause cancer when their function is disrupted. Their model has demonstrated that certain characteristics of XCID likely predispose patients to leukemia, and suggests that gene therapy for other disorders may not be as risky as that for XSCID. They hope this model will allow for the discovery of more genes associated with T-cell leukemia due to gene therapy, making treatments safer and more effective.

Despite successful results with gene therapy in a French trial of 11 patients with X-linked severe combined immune deficiency (XSCID), three of the patients developed leukemia as a result of the gene therapy. Their leukemia was a result of the gene therapy vectors disrupting the normal genes in their cells. Vectors are the delivery vehicles that carry the therapeutic genes to the cells. Since then, this has become a major concern in the field of gene therapy, making it critical for researchers to better understand what caused the leukemia, and how to make new vectors safer.

Improving the safety of gene therapy vectors

A study reporting the use of chromosomal insulators to improve the safety of using gene therapy vectors was presented today at the 8th Annual Meeting of the American Society of Gene Therapy (ASGT) in St. Louis.

Gene therapy using retrovirus vectors holds great promise for the treatment of human disease. However, as seen in the XSCID trial, where three patients developed leukemia, there is a risk for serious side effects when the gene therapy vectors used in the delivery of the therapeutic genes disrupt the normal genes in the cells of the patient.

David W. Emery, PhD, and colleagues from the University of Washington demonstrated that a class of DNA elements called chromosomal insulators can significantly reduce the risk of such serious side effects. Chromosomal insulators have the ability to block the interaction between genes in neighboring parts of the chromosomes, effectively insulating one portion of the chromosome from another.

Researchers exposed cells that did not normally cause tumors to retrovirus gene therapy vectors that contained and did not contain a chromosomal insulator. They found that the use of chromosomal insulators significantly reduced the rate with which these cells formed tumors. These findings represent a significant means of improving the potential safety of using gene therapy vectors to treat human disease.

Clinical trial for cancer shows promise

A Phase I clinical trial using a modified virus vector to treat cancer showed promising results, according to findings presented today at the 8th Annual Meeting of the American Society of Gene Therapy (ASGT) in St. Louis.

Jennifer Hu, MD, from Imperial College School of Science and Medicine, and colleagues, treated 30 patients suffering from metastic cancer with a modified herpes simplex virus oncolytic virus vector. The herpes virus replicates very quickly in tumors due to the expression of a specific viral gene and also produces a protein called GM-CSF, which has previously been shown to stimulate host immune response.

The overall goal of the trial was to treat the patients through the use of multiple injections of the modified virus vector directly into the tumor mass at escalating doses to determine the safest and most effective dose. The treatment was effective in decreasing the size of both the primary tumor and smaller tumors close to the injection site in some of the patients.

The results of the clinical trial showed that the modified virus vector was well tolerated, leading researchers to test its effectiveness in a Phase II clinical trial.

The American Society of Gene Therapy is a professional non-profit medical and scientific organization dedicated to the understanding, development and application of gene and related cell and nucleic acid therapies and the promotion of professional and public education in the field.

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