ASGT Press Release

February Issue: Molecular Therapy

SAN DIEGO-This is the press release for the February issue of Molecular Therapy, the official journal of the American Society for Gene Therapy. The journal is published monthly by Academic Press, a Harcourt Science and Technology Company.

Electronic access to these articles and to those from the January issue is free through March 31, 2000. They can be found on the journal's home page (http://authors.elsevier.com/JournalDetail.html?PubID=622922&Precis=DESC). The February issue will be available by mid-day Wednesday, February 23. Please contact the editor (information below) with any comments or questions.

Gene therapy muscles its way into LGMD treatment
"Rescue of skeletal muscles of gamma-sarcoglycan-deficient mice with adeno-associated virus-mediated gene transfer" Mol. Ther. 1 (2): 119-129.

"Muscular Dystrophy" is actually a family of several different genetic diseases that affect skeletal and cardiac muscle. The genetic defects associated with muscular dystrophy include mutations in the dystrophin gene and in the genes of its associated glycoproteins, the sarcoglycans. In humans, mutations in the sarcoglycan genes (alpha, beta, gamma, and delta) have been identified with limb-girdle muscular dystrophy (LGMD).

In this issue of Molecular Therapy, H. Lee Sweeney of the University of Pennsylvania School of Medicine and his collaborators demonstrate that transfer of the gamma-sarcoglycan gene into the limbs of mice lacking the native gene can rescue the dystrophic pattern of muscles undergoing rapid degeneration. This mouse model is particularly apt for study of LGMD gene therapy, as the degeneration of muscle parallels the severe clinical and histopathological features of human LGMD. The gamma-sarcoglycan gene was made with a recombinant adeno-associated virus, a type of virus that has minimal immune system effects.

There are two caveats to this work. First, it is clear that the earlier the intervention happens, the more successful it is. In other words, the researchers found that efficient gene transfer does not occur in advanced disease. Secondly, it is still unclear if the immune response against the newly introduced protein will eventually cause further problems, an issue that is controversial in many gene therapy studies where a new protein is introduced by translation of the transferred gene. Nevertheless, this study holds great promise for fighting back against at least one form of human muscular dystrophy.

Contact:
Dr. H. Lee Sweeney
Department of Physiology
University of Pennsylvania School of Medicine
A700 Richard Building
3700 Hamilton Walk
Philadelphia, PA 19104
215-898-0475 (fax)
lsweeney@mail.med.upenn.edu

Curing hemophilia in dogs
"Sustained expression of therapeutic levels of factor IX in hemophilia B dogs by AAV-mediated gene therapy in liver" Mol. Ther. 1(2): 154-158.

Hemophilia is a particularly attractive disease for gene therapy in these early days of the field's development. Even a small amount of the missing clotting factor can result in marked clinical improvement, and relatively high amounts of the protein do not appear to have detrimental effects. Furthermore, as a blood disorder there are a variety of possible target cells that, when genetically altered, could provide the protein to the blood stream.

Inder Verma of the Salk Institute and his colleagues describe one stunningly successful experiment in this issue of Molecular Therapy. They treated dogs suffering from hemophilia B (i.e., dogs lacking clotting factor IX) with a recombinant adeno-associated virus containing the gene for factor IX, by direct injection into the portal vein of the liver. Following the single injection, the treated dogs have continued to express therapeutic levels of the clotting factor for over 7 months. In addition, no antibodies to the canine factor IX have been detected, nor have any significant and persistent liver abnormalities arisen.

This study helps establish both the safety and the efficacy of recombinant adeno-associated virus for liver transfer of genes related to hemophilia, and suggests strongly that this approach could work in humans afflicted with the disease.

Contact:
Dr. Inder M. Verma
Laboratory of Genetics
The Salk Institute
10010 North Torrey Pines Rd.
La Jolla, CA 92037
858-558-7454 (fax)
verma@salk.edu

Decreasing atherosclerosis without decreasing cholesterol
"Hepatic expression of apolipoprotein E inhibits progression of atherosclerosis without reducing cholesterol levels in LDL receptor-deficient mice" Mol. Ther. 1 (2): 189-194.

Apolipoprotein E (apoE) is an important player in regulating plasma lipoproteins. Derived primarily from the liver, plasma apoE is important for the clearance of chylomicrons and VLDL remnant lipoproteins from the circulation. However, a growing body of literature suggests that macrophage-derived apoE plays a role in inhibiting atherosclerosis independent of its effects on plasma lipid concentrations.

Daniel J. Rader of the University of Pennsylvania and his collaborators describe experiments in this issue of Molecular Therapy aimed at determining whether overexpression of apoE in the liver can play an antiatherogenic role independent of its well-defined function in regulating lipoproteins. They treated mice lacking the LDL receptor (a model for human familial hypercholesterolemia) with an adenoviral vector containing the human apoE gene. Subsequent liver expression of apoE had no discernible effect on the plasma lipid levels in these mice, but the development of atherosclerosis was remarkably inhibited. This suggests that therapeutic approaches, including gene therapy, aimed at raising plasma apoE levels may provide a novel systemic treatment for atherosclerosis in humans.

Contact:
Dr. Daniel J. Rader
Institute for Human Gene Therapy
University of Pennsylvania School of Medicine
Philadelphia, PA 19104
215-573-6725 (fax)
rader@mail.med.upenn.edu

Beating swords into plowshares
"Transduction of human PBMC-derived dendritic cells and macrophages by an HIV-1-based lentiviral system", Mol. Ther. 1 (2): 171-179.

Although antigen-presenting cells such as dendritic cells and macrophages are attractive targets for gene therapy of infectious disease and cancer, transduction of these cells with most current gene transfer methods has proven "iffy" at best. Given the pivotal role dendritic cells play in stimulating antigen-specific T cells, a better vector would be a huge boon to the field of cancer immunotherapy. Furthermore, efficient ways to target macrophages is critical to developing effective anti-HIV therapies.

In this issue of Molecular Therapy, Si-Yi Chen of the Baylor College of Medicine and his colleagues describe a lentiviral vector with just these properties. By specifically altering an HIV virus, the researchers were able to create a vector that infected both dendritic cells and macrophages efficiently without the attendant side effects associated with the wild-type virus. This work opens the way to a host of possible cancer and HIV-related therapies, and suggests that lentiviral vectors will make an important contribution to the success of gene therapy.

Contact:

Dr. Si-Yi Chen
Center for Cell and Gene Therapy
Baylor College of Medicine
One Baylor Plaza
Houston, TX 77030
713-798-1230 (fax)
sychen@bcm.tmc.edu

Other articles of interest in the February issue:

• Adenovirus-mediated inducible gene expression in vivo by a hybrid ecdysone receptor

• Intrakines -- Evidence for a trans-cellular mechanism of action

• Lymphoid development and function in X-linked SCID mice after stem cell therapy

• Phase I study of adenoviral delivery of the HSV-tk gene and gancyclovir administration in patients with recurrent malignant brain tumors

This month's editorial suggests early lessons to be derived from the ongoing investigation by the FDA of the University of Pennsylvania gene therapy program.

For further information, contact:

Fintan R. Steele, Ph.D.
Editor, Molecular Therapy
c/o Academic Press
525 B St. Suite 1900
San Diego, CA 92101
Fax: 619-699-6283
E-mail: fsteel@acad.com

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