ASGT Press Release

October Issue: Molecular Therapy

This is the press release for the October 1, 2001, issue of Molecular Therapy (Volume 4, Number 4), 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).

Following the light
A primary goal of successful gene therapy is getting the transferred gene expressed in the right place and at a therapeutic level. To date, the most reliable way to check this in animal models has been through postmortem analyses (tissue staining or enzyme activity assays). Because of great variation from animal to animal, this makes it very difficult to draw broad conclusions. However, several laboratories have begun to look at ways to determine where gene therapy vectors go and how well they are expressed in real time in living animals, a technique that will accelerate the development of robust gene therapies.

In this issue, Sanjiv Gambhir and his collaborators at UCLA describe a noninvasive system to track transgene expression in the skeletal muscle of living animals. Using a cooled charged coupled device (CCD) camera and the firefly luciferase gene as a "reporter," the researchers demonstrate that they can accurately and reproducibly track the location, magnitude, and persistence of gene expression without harm to the animals. In addition to providing fascinating images of gene expression in living tissues, the continued development of such tools can dramatically improve both the quality and speed of evaluating different gene therapy approaches in animal models.

"Noninvasive optical imaging of firefly luciferase reporter gene expression in skeletal muscles of living mice." Wu, et al. Molecular Therapy 4:4, 297-306

Gene therapy to block diabetes
Autoimmune diabetes (type 1 diabetes) results from the destruction of pancreatic beta cells mediated by T cells that react against normal beta cell proteins for unknown reasons. Previous work has shown that dampening this misguided immune response by providing increased concentrations of the cytokine proteins interleukin-4 (IL-4) and interleukin-10 (IL-10) can spare the beta cells and prevent the development of type 1 diabetes. However, this approach is impractical for many reasons, including the difficulty of preparing the protein, the need for repeated administration, and the creation of more immune and toxicological problems than it solves. A gene therapy approach to provide these cytokines in the place and amount they are needed is a very attractive alternative approach.

To that end, Sung Wan Kim and his University of Utah coworkers present experiments in this issue of Molecular Therapy that successfully transfer DNA plasmids containing the genes encoding IL-4 and IL-10 into mice with autoimmune diabetes. Following only one injection, 75% of mice that would normally have progressed to severe diabetes remained free of the disease. Further refinement of this approach holds great promise for treating not only type 1 diabetes, but perhaps other diseases that require blocking an aberrant immune response.

"Combined administration of plasmids encoding IL-4 and IL-10 prevents the development of autoimmune diabetes in nonobese diabetic mice." Ko et al., Molecular Therapy 4:4, 313-316.

Holding Parkinson's disease at bay
Despite significant work in both understanding and treating Parkinson's disease, the precise cause of this devastating illness remains unknown. Knowledge of the biochemical pathway for dopamine, the neurotransmitter made by the midbrain neurons that degenerate in the disease, has led to some treatments. For example, administration of L-DOPA, the dopamine precursor, is efficacious early in disease but declines in effectiveness as disease progresses and can be toxic.

Despite uncertainty as to the exact molecular mechanism of Parkinson's disease, gene therapy aimed at fortifying the dopamine biochemical pathway could prove invaluable in delaying or even preventing the onset of symptoms. Krys Bankiewicz of the University of California, San Francisco, and a group of collaborators from several institutions publish exciting work in which they transfer a gene encoding a critical enzyme in the dopamine pathway into the affected areas of a rat Parkinson's disease model, enhancing and prolonging the protection afforded by L-DOPA drug treatment (the transferred gene encodes L-amino acid decarboxylase, which catalyzes the formation of dopamine from L-DOPA). Perhaps the most important observation in this work is the demonstration that the improvement is behavioral, not just biochemical, suggesting this as an important approach for restoring responsiveness to L-DOPA in Parkinson's patients who are beginning to fail drug treatment or who cannot tolerate high doses of the drug.

"Functional effect of adeno-associated virus mediated gene transfer of aromatic L-amino acid decarboxylase into the striatum of 6-OHDA-lesioned rats." Sanchez-Pernaute, et al. Molecular Therapy 4:4, 324-330.

On the cover:
From dark to light: gene therapy for protoporphyria
The erythropoietic porphyrias (EP) are a group of related genetic diseases marked by defects in the enzymes of the blood heme biosynthetic pathway, which results in accumulation of toxic porphyrins in tissues. In severe forms, extreme photosensitivity of the skin develops, condemning sufferers to a life in the dark. One of these, erythropoietic protoporphyria (EPP), is caused by a defect in ferrochelatase, the last enzyme of the heme pathway. Although previous gene therapy approaches have been tried, these have  proven impractical for a variety of reasons.

In this issue, Francois Moreau-Gaudry and an international group of researchers report a novel approach to EPP in a mouse model of the disease using a specialized form of lentiviral vector to deliver the ferrochelatase gene into hematopoietic stem cells from donor EPP mice, which were subsequently transplanted into EPP recipients. Their approach, which limited the new gene expression to erythroid cells, corrected the skin photosensitivity in these mice as well as well as most of the other clinical and biochemical manifestations of the disease. These exciting results not only underline the potential promise of lentiviral vectors for gene therapy, but open the door to successful clinical protocols for the family of EP diseases.

"Gene therapy of a mouse model of protoporphyria with a self-inactivating erythroid-specific lentiviral vector without preselection." Richard et al., Molecular Therapy 4:4, 331-338.

Commentary:
Lentiviral vectors approach the clinic but fall back
Lentiviral vectors, including those based on HIV, offer great potential for effective gene therapy of a variety of diseases. The first human protocol for clinical use of these vectors, for the treatment of AIDS, was recently presented to the Recombinant DNA Advisory Committee (RAC) of the National Institutes of Health. Given the large number of scientific questions as well as concerns about safety and the public understanding of these vectors, the RAC has asked the sponsors of the trial to provide additional information before proceeding to the clinic. Greg Podsakoff of Childrens Hospital Los Angeles reviews the RAC hearing on this particular protocol and comments on the specific issues facing lentiviral vectors for clinical use.

A history of gene therapy
This issue of Molecular Therapy sees the launch of a new series of articles that examine the important and often stormy events that have shaped gene therapy. The series, edited by Theodore Friedmann of the University of California-San Diego, will attempt to not only relate important events and papers, but to put  them in the context of their influence on current practices and beliefs.

The first installment, written by Dr. Friedmann, looks at the work of Stanfield Rogers, who was the first to use viruses to transfer potential therapeutic genes to humans. It is a fascinating story, and one that has lessons for the science as well as the social and ethical policies related to this new medical approach.

Future installments, written by experts in their respective areas, will focus on early expectations, dashed hopes, public concerns, and the basic science behind some of the most widely used vectors. Although relatively young, gene therapy's history is of interest not only to researchers and clinicians but also to anyone curious about the interaction of forces that have drive modern medicine.

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.

Fintan R. Steele, Ph.D.
Editor, Molecular Therapy
Executive Editor, Genomics
Academic Press
15 E. 26th St. 15th Floor
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fsteele@acad.com
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http://www.academicpress.com/genomics

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