ASGT Press Release 

New research on gene therapy clinical trials, today's findings from the ASGT 7th Annual Meeting

Researchers note immune responses to AAV and FIX

MINNEAPOLIS - A study reporting the results of a clinical trial using Adeno Associated Virus (AAV) vectors in two patients with Hemophilia B was presented today at the 7th Annual Meeting of the American Society of Gene Therapy (ASGT).

AAV vectors are present in many humans, but have never been associated with any disease, making them an excellent gene transfer vehicle. Hemophilia B is caused by a deficiency of the blood clotting protein, Factor IX (FIX), which is normally made in the liver and secreted into the blood stream. Previous research has shown that the FIX gene could be used to replace the AAV viral genes, allowing AAV virus proteins to deliver the FIX gene to the cells.

Katherine A. High, MD, Children's Hospital of Philadelphia, and colleagues infused the patients with a dose of AAV-FIX that had previously been shown to be both therapeutic and safe in animals. While initial results of the study were encouraging, as levels of 3% and nearly 12% of newly produced FIX levels were measured in the patients, the FIX levels dropped to undetectable levels after several months.

Researchers showed that both patients had an immune response against the AAV and the newly produced FIX. The goal of future research is to determine how the immune response of the patients contributed to the elimination of FIX producing cells, in the hope to determine whether patients can achieve therapeutic FIX levels.

Alternative therapy for HIV

Researchers have developed an alternative therapy for HIV/AIDS, according to a study presented today at the 7th Annual Meeting of the American Society of Gene Therapy (ASGT).

Boro Dorpulic, PhD, Johns Hopkins School of Medicine, and colleagues removed the viral genes from the HIV virus and substituted a DNA sequence that is complementary to the HIV RNA, called an antisense gene. The antisense gene uses HIV proteins to introduce the new virus to CD4+ T-lymphocytes, the cells HIV prefers to infect. When the antisense gene is made into RNA, it will pair with regular HIV RNA and block the translation of HIV RNA into protein, effectively preventing the spread of HIV in patients whose CD4+ T-cells carry the introduced virus.

In a clinical trial, CD4+ T-cells were taken from five patients with AIDS, and exposed to the antisense virus, which expanded to more than 10 billion cells that were given back to the patients. So far, in the first two patients, the preliminary analysis has shown a significant reduction in the amount of HIV in their blood stream to nearly undetectable levels.

Continued progress in treating SCID

A study showing continued progress in the development of gene therapy as an effective treatment for severe combined immune deficiency (SCID) was presented today at the 7th Annual Meeting of the American Society of Gene Therapy (ASGT). The most common form of SCID, also known as "bubble boy" disease, is Adenosine Deaminase (ADA) deficiency.

Alessandro Aiuti, MD, PhD, San Raffaele Telethon Institute for Gene Therapy, Italy, previously treated four patients with ADA-deficient SCID by inserting human ADA gene using retroviral vectors, restoring immunity in all four patients. In the present study, the researchers analyzed the sites where the ADA retroviral vector had integrated into the chromosomal DNA of the patients using genomic techniques.

They found that the vector was integrated into a large number of different sites in T cells, consistent with efficient gene delivery to stem or progenitor cells that made T cells. There was no evidence that the integrated vectors were causing any harmful effects.

Safe genetic transfer

A clinical trial involving the safe genetic transfer of the gene G156A-MGMT was presented today at the 7th Annual Meeting of the American Society of Gene Therapy.

Preclinical models in mice and dogs has shown that the gene G156A-MGMT can provide stem cells with very high levels of drug resistance, compared to normal stem cells not carrying the gene.

Stanton Gerson, MD and colleagues from Case Western Reserve University School of Medicine in Cleveland collected peripheral blood cells from five patients with advanced malignancies and exposed them to a retrovirus containing the G156A-MGMT gene. The blood cells were then infused into the patients, who were then treated with chemotherapy, using a combination specifically designed to provide resistance to the stem cells that have the new gene.

Researchers reported no complications related to the cell infusion or chemotherapy administration. Safe genetic transfer into hematopoietic stem cells has important clinical applications for the correction of genetic disorders, providing new sources of proteins to treat diseases and to protect stem cells from toxic exposures.

Adenoviral-p53 therapy may benefit cancer patients

Adenviral gene therapy with the p53 protein was safe and well tolerated in patients with advanced cancers, according to a study presented today at the 7 th Annual Meeting of the American Society of Gene Therapy (ASGT).

The p53 protein plays a central role in telling damaged cells to stop dividing or to give the damaged cell the signal to die. However, many tumors have mutated the p53 gene, resulting in its loss of function. In this study, researchers have developed an adenovirus vector that has had some of the adenovirus genes replaced with the p53 gene.

In the study, Louis A. Zumstein, PhD and colleagues from Introgen Therapeutics, Incorporated, utilized the adenoviral vector in 14 clinical trials of patients with advanced cancers of the lung, head, neck as well as other forms of the disease. They administered over 3000 doses of adenoviral p53 to 445 patients, most by direct injection into the tumor, and in some patients by injection into the bloodstream. In some of the trials, it was used in addition to standard chemotherapy.

As expected, the infusion of adenoviral p53 caused many of the patients to have a fever for a day or two, some pain at the site of the injection, or an upset stomach for a short time. However, compared to the effects of most chemotherapy, the side effects were considered mild, suggesting its use as a monotherapy or in combination with chemotherapy.

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 nearly 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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