ASGT Press Release

September Issue: Molecular Therapy

This is the press release for the September 1, 2001, issue of Molecular Therapy, the journal of the American Society of Gene Therapy (ASGT). Molecular Therapy is owned and copyrighted by the ASGT, and published monthly by Academic Press, an imprint of Elsevier Science.

This information is not embargoed (see embargo policy below). Please cite Molecular Therapy as the source of this information.

All questions should be directed to the Editor (contact information below).

Editorial: Stem cell déjà vu?
The extensive press coverage of the stem cell debate is, in general, a good thing. However, stem cell proponents are perhaps overselling the potential of stem cells. The same thing happened ten years ago with gene therapy. The higher expectations are raised, the further and harder they can fall. Several major news outlets are currently preparing stories on this aspect, and this editorial could be useful in understanding the issues at stake.

"Are the Benefits of Stem Cells Being Oversold?" Inder M. Verma. (2001). Molecular Therapy 4: 161.

Progress in hemophilia research - part one
A cluster of papers in this month's issue of Molecular Therapy report progress on two different fronts in treating hemophilia by use of an adeno-associated virus (AAV) containing the gene for the missing clotting factors.

Of significant interest - and concern - to gene therapists is the question of whether providing the gene that encodes a missing protein will trigger the immune system to attack the therapeutic protein as foreign. This phenomenon has been noted not only in hemophilia research but in other gene therapy applications. In the case of hemophilia, providing a missing clotting factor can cause the body's defenses to attack this "foreign" invader, thus preventing therapeutic efficacy.

Two papers in this issue of Molecular Therapy describe a potential way around this problem. The researchers describe experiments that demonstrate that both dogs and mice that carry deletions in the gene for clotting Factor 9 (resulting in hemophilia B) can be treated intramuscularly with AAV-containing the functional Factor 9 gene without an immune response if, at the time of the gene therapy treatment, they are also given the immunosuppressive drug cyclophosphamide. This transient immune suppression appears to effectively reduce the immune response, and thus increase the therapeutic potential of the transferred gene.

These findings may have direct relevance not only to hemophilia trials that are currently ongoing but to many gene therapy applications underway or being considered.

Herzog, et al. (2001). "Muscle-directed gene transfer and transient immune suppression result in sustained partial correction of canine hemophilia B caused by a null mutation." Molecular Therapy 4: 192-200.

Fields, et al. (2001). "Risk and prevention of anti-factor IX formation in AAV-mediated gene transfer in the context of a large deletion of F9." Molecular Therapy 4: 201-210.

Progress in hemophilia research - part two
AAV is one of the better-characterized and most used vectors in current gene therapy research. However, there have been some difficulties in getting enough of the virus (and thus its genetic payload) into the cells of interest. To date, studies have focussed primarily on one "serotype" of AAV, known as AAV-2. This serotype is used not only in much of the pre-clinical research, but in the human clinical trials of hemophilia and other diseases. In the hemophilia trials, the intramuscular injection of AAV containing the gene for the missing clotting factor has yielded some improvement, but not a cure. One possibility is that the AAV-2 does not efficiently infect the muscle cells.

In this month's Molecular Therapy, a group of researchers from the University of North Carolina provide striking evidence that the intramuscular delivery of another serotype, AAV1, increased the expression of factor 9 in treated hemophilic mice 100 to 1000 times over AAV-2-treated mice, i.e., to sustained curative levels. Furthermore, they did not see any significant immune response to the introduced gene. The nature of this last observation is uncertain, and further research will have to be done to determine the role of the vector vs. the product of the delivered gene in generating the immune response. Nevertheless, these findings have obvious and immediate implications for current and future trials.

Chao, et al. (2001). "Sustained and complete phenotype correction of hemophilia B mice following intramuscular injection of AAV1 serotype vectors." Molecular Therapy 4: 217-222.

A TRAIL to cancer gene therapy
Cancer is, at its most basic, out-of-control cellular growth. Many anti-cancer agents have been exploited for their ability to persuade tumor cells to cease their program of mindless growth and turn instead to program of cell death (apoptosis). Certain naturally occurring proteins can also trigger apoptosis (indeed, they are part of the normal tightly regulated cellular machinery for balancing growth and death). One of these, known as TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) has shown some promise in systemic cancer treatment without major toxic side effects. However, treatment with TRAIL protein is transient, and insufficient to prevent eventual tumor outgrowth. However, providing the TRAIL gene directly to the site of the tumor could result in sustained and effective death of tumor cells.

In this issue, a research team from the University of Iowa describes such a gene therapy application. The TRAIL gene is delivered via an adenovirus vector directly to a prostate cancer tumor transplanted into immunodeficient mice. The researchers show that the tumor cells are effectively forced into an apoptotic program, where normal prostate epithelial cells from the implant are unharmed. This work not only confirms that TRAIL is a potentially effective anti-cancer molecule, but that a gene therapy approach could be the best way to attack prostate and other solid tumors in vivo.

Griffith and Broghammer. (2001). "Suppression of tumor growth following intralesional therapy with TRAIL recombinant adenovirus." Molecular Therapy 4: 257-266.

Following the Light
One significant difficulty in any gene therapy approach is knowing where the vector/gene combination is going and how effectively it is taken up and expressed when it gets there. Although there has been some progress in "in vivo" imaging, there has never been a systematic comparison of methods of delivery, organ specificity, and duration of gene expression. Nevertheless, the development of such tools could lead to even faster evaluation of new treatment approaches, and thus concentrating on translating the most successful ones to the clinical setting.

A research group from the Hebrew University in Jerusalem describes an extensive series of experiments in which they trace the expression of therapeutic genes using a new light-detection cooled charged-coupled device (CCCD) camera in living mice and rats. Besides providing some very cool pictures, this approach offers a simple, reproducible, and directly applicable method for continuous monitoring of a wide array of gene delivery systems in living animals.

Honigman, et al. (2001). "Imaging transgene expression in live animals." Molecular Therapy 4: 239-249.

Also of interest in this issue:
Directing AAV-2 specifically to human vascular endothelial cells
Modifying HIV-1 for greater gene transfer efficiency and expression
Altering adenovirus for enhanced ovarian cancer chemotherapy mediation (cover photo)
Regulating the expression of an exogenously supplied growth hormone gene

EMBARGO POLICY:
Molecular Therapy considers the embargo lifted upon editorial acceptance of a manuscript (i.e., the decision of the editor to accept a manuscript following successful peer review and revision). We make every effort to have manuscripts published electronically before print. Manuscripts still under review should not be reported as being published in Molecular Therapy.

For information contact:
Fintan R. Steele, Ph.D.
Editor, Molecular Therapy
Executive Editor, Genomics
Academic Press
15 E. 26th St. 15th Floor
New York, NY 10010
212-592-1023 phone
646-935-3742 fax
fsteele@acad.com
http://authors.elsevier.com/JournalDetail.html?PubID=622922&Precis=DESC
http://www.academicpress.com/genomics

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