Inaugural Issue: Molecular Therapy

SAN DIEGO-The first issue of Molecular Therapy, the official journal of the American Society for Gene Therapy, is out! This new monthly journal, published by Academic Press, features top scientific articles covering basic research, methodological advances, and clinical trials broadly relevant to the nascent discipline of gene therapy. In addition, each issue will contain expert commentaries and reviews on both the scientific and social/ethical issues facing the field as it moves closer to common medical practice.

Of the several significant scientific hurdles facing genetic medicine, the most pressing is the design of effective and safe vectors -- viral and nonviral -- for delivering genes of interest to the correct cells and tissues. Thus, many articles in the first issue (and for the foreseeable future) focus on the progress being made with a growing variety of vectors.

The following are descriptions of a few of the papers in this inaugural issue. Copies of galley proofs are available by fax (PDF files will be available soon!). If you are interested in receiving this press release, please e-mail the Editor, Fintan Steele, with your request.

Molecular Therapy Volume 1 No. 1

Getting adenoviral vectors into shape 
Article: 'Type-specific epitope locations revealed by x-ray crystallographic study of adenovirus type-5 hexon, ' pp.18-30. 
Commentary: 'Rational design of viral vectors based on rigorous analysis of capsid structures,' pp. 3-4.

One hallmark of a 'successful' vector is overcoming the host's immune response to the invader. In the case of adenovirus, the response is directed against the viral hexon coat protein. Rational design of adenoviral vectors requires an understanding of the basic structure of this protein. John J. Rux and Roger M. Burnett of The Wistar Institute report the successful solution of the hexon protein from adenovirus type-5, the most widely used vector in adenoviral gene therapy. Their report not only suggests new approaches to evading the immune response, but also proposes new ways to specifically tailor adenoviral vectors to target specific tissues or cell types.

In an accompanying commentary, David T. Curiel of the University of Alabama at Birmingham, discusses the importance of the adage 'structure precedes function' in designing efficient and safe vectors for gene delivery.

Herding cat viruses 
Article: 'Efficient transduction of nondividing cells by optimized feline immunodeficiency virus vectors,' pp. 31-38.

Another group of attractive vectors for possible gene therapy applications are the lentiviruses, of which HIV is the best known example. The ability of these viruses to infect a wide variety of non-dividing cell types suggests their utility not only in repairing defective gene function but in studying basic cellular physiology. Garry Nolan and his colleagues from Stanford University describe an optimized set of vectors based on feline immunodeficiency virus (FIV) which shares HIV's ability to infect non-dividing human cells but not its human pathogenicity. These so-called FELIX vectors can infect a variety of human cells, even some not easily infected by HIV, and thus hold out great promise for a variety of research and clinical applications.

Getting naked 
Article: 'Human T lymphocyte genetic modification with naked DNA,' pp. 49-55

The immune response to viral vectors, in addition to other problems, has helped fuel research into non-viral gene transfer methods. One such approach is direct injection of 'naked' DNA. Michael Jensen and his collaborators from the City of Hope National Medical Center and Beckman Research Institute describe using this approach to genetically modify primary human T lymphocytes. Although this has been attempted before, the protocols designed by Jensen et al. succeeded. They are using these methods in a phase I clinical trial to modify T cells from patients with recurrent/refractory lymphoma for direct cellular immunotherapy.

In vivo test tubes 
Method: 'Metabolic biotinylation of recombinant proteins in mammalian cells,' pp. 96-104.

Modern biologists use a number of chemical tricks to purify or image molecules of interest. One widely employed method takes advantage of the natural attraction between biotin (vitamin H) and avidin (a protein found in egg albumin) to detect macromolecules. To date, protein biotinylation has only been used successfully in vitro, and its use is limited by side effects of the chemical manipulations required.

In this issue of Molecular Therapy, Michael A. Barry and M. Brandon Parrott of the Baylor College of Medicine describe a series of elegant experiments in which they demonstrate that biotin-tagging of proteins can be accomplished in vivo in animal cells using the cells' inherent biotinylation metabolic machinery. By injecting naked DNA containing a gene encoding a protein with a 'biotin acceptor' tag into either cells or living mice, the researchers demonstrate that the corresponding biotinylated protein can easily be purified from both.

The possible applications of this metabolic biotinylation system go far beyond protein purification. Of particular interest is the use of this method for drug and gene therapy targeting, in particular the enhancement of vector specificity and infectivity. Indeed, this method will undoubtedly become a standard by which others are measured in many areas of molecular biology.

Spare parts 
Review: 'Tissue engineering,' pp 12-15. 

Several weeks ago, a full page advertisement from a coalition of anti-biotechnology groups appeared in the New York Times. The most prominent feature of this ad was a picture of a mouse with what appeared to be a human ear growing out of its back. This Frankensteinian image was aimed at terrifying readers into believing that scientific advance was out of control. However, the facts behind the photo reveal no evil intent. The 'ear' is simply a 'scaffolding' molded to look like an ear into which cartilaginous cells can grow: a cosmetic boon to those who may have lost their ear in an accident or a fit of artistic expression. Robert Langer of the Massachusetts Institute of Technology outlines the incredible advances in tissue engineering in a fascinating review of the field.

Among the other scientific articles in this inaugural issue are descriptions of advances in other viral vectors (adeno-associated virus, herpes simplex virus), gene therapy approaches to specific disease (head and neck squamous cell carcinoma, mucopolysaccharidosis, cystic fibrosis) and specific methodological breakthroughs (e.g., enhanced angiogenesis imaging).

Regulatory/social/ethical issues
The recent meeting of the Recombinant DNA Advisory Committee (RAC) of the NIH was covered extensively in the popular press. However, most of the reporting centered on the alleged lapses by University of Pennsylvania researchers in a clinical trial in which one patient tragically died, perhaps as a direct result of the adenovirus vector used. In fact, there was a helpful discussion that focussed on unresolved scientific and clinical issues facing the gene therapy field. These issues are outlined in a commentary by Fintan Steele, editor of Molecular Therapy.

Another growing concern is the relationship of academia and drug/biotech companies in the discovery and development of robust therapies. Ted Friedmann of the University of California, San Diego examines this often-uneasy partnership and suggests avenues of rapprochement.

Finally, the vital need for rigorous adverse effect reporting in ongoing clinical trials is underlined in an ASGT policy statement given by president Savio L.C. Woo to the RAC, which is reproduced in this issue of Molecular Therapy.

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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