ASGCT Press Release

This is the press release for the May 2002, issue of Molecular Therapy, the Journal of the American Society of Gene Therapy (ASGT). Academic Press, an imprint of Elsevier Science, publishes Molecular Therapy monthly. 

Please credit Molecular Therapy as the source of this information. 

The embargo is lifted upon your receipt of this message (see below for our embargo policy). All questions should be directed to the editor.

The Cerberus Project

(Cover photo)
("Cabo II: Immunology and Gene Therapy." (2002). Molecular Therapy 5: 486-491.)

Gene therapy holds great promise, but this promise has, for the most part, not translated into real medical interventions. The primary obstacle to most advances has been the "three-headed" immune system (cellular, humoral, and innate immunity). Early gene therapy research focused on making vectors that could evade immunity, but gene therapists are learning that the immune system cannot easily be fooled. A group of gene therapists and immunologists gathered recently in Cabo San Lucas, Mexico, to discuss what immune issues face effective gene therapy, and came to some consensus on how to move the field forward. Specific points of action include not just evasion techniques, but ways to bend immunity to serve gene therapy rather than defeating it. The commentary in this issue both reviews the discussions at "Cabo II" and outlines the proposals (i.e., "The Cerberus Project") that the participants believe will move gene therapy closer to realizing its immense potential.

Tiny bubbles

("Fetal Gene Transfer by Intrauterine Injection with Microbubble-Enhanced Ultrasound." Endoh, M., et al. (2002). Molecular Therapy 5: 501-508.)

In utero fetal gene transfer holds out not only the hope for treating inherited genetic diseases early in development, but will also be an indispensable tool for understanding how primitive cells regulate genes in the course of differentiating to adult tissue. However, the most effective vectors for in utero gene delivery so far have been viral vectors, which have disadvantages for both therapy and research investigations, i.e., toxicity, extraneous genetic information, etc. Nonviral approaches have also been examined, but perhaps the best option is "naked" DNA, i.e., just the genetic material. However, this approach has suffered from very poor transfer efficiencies.

To this end, Yasufumi Kaneda of the Osaka University Medical School and his collaborators take advantage of a technique currently in use in vascular gene delivery strategies: microbubble-enhanced ultrasound or the "shotgun method" (SGM). Using this established clinical tool to deliver naked DNA to fetal mice, the researchers show that they can easily transfer genes to a large number of different fetal tissues safely. In addition, the concentration of DNA transferred is much lower than previous approaches. 

Although these results suggest that this tool can be adapted immediately to basic developmental research studies (particularly to normal stem cell differentiation), the possibility of clinical gene transfer to the fetus raises a host of ethical as well as scientific questions. Although the researchers did not see gene alteration in the germ line of the experimental animals, this remains a concern that must be examined in large animal models. In addition, the degree of risk to the fetus from this kind of procedure is unclear, although in the mice studied it was minimal. 

A genetic bandage

("Delivery of FGF Genes to Wound Repair Cells Enhances Arteriogenesis and Myogenesis in Skeletal Muscle." Doukas, J., et al. (2002). Molecular Therapy 5: 517-527.)

The repair of injured or ischemic muscle is an amazing biochemical process. It is initiated and driven in large part by migratory macrophages and fibroblasts that infiltrate the injured area and release a mix of growth factors. This results in the elaborate mixture of angiogenesis, arteriogenesis, and myogenesis working in concert to repair the injury. Although several well-studied angiogenic genes/proteins can play a role (e.g., VEGF), none are sufficient in themselves to initiate the whole spectrum of responses necessary for successful and complete repair. 

John Doukas and his collaborators at Selective Genetics, Inc., in San Diego, describe a gene therapy approach to speed and enhance the complicated process of tissue repair. By expressing fibroblast growth factor (FGF) genes in a specialized external matrix, then transfer of the matrix/gene mix into the site of injury, they demonstrate significant improvement of skeletal muscle injury. This kind of approach should prove useful not only for the healing of accidental injuries or post-surgical repair, but also for treating ischemic conditions in both cardiac and skeletal muscle. These studies also shed additional light on the normal healing processes, which are still incompletely understood.

An endostatin success?

(" Endostatin Gene Transfer Inhibits Joint Angiogenesis and Pannus Formation in Inflammatory Arthritis." Yin, G., et al. (2002). Molecular Therapy 5: 547?554.)

Last month, Molecular Therapy featured two articles demonstrating that high systemic expression of the endostatin gene failed to eliminate tumors, despite earlier published work using the protein itself to the contrary. In this month's issue, a group of researchers led by Wang Min at the University of Rochester Medical Center describe a set of experiments that suggest that transfer of the endostatin gene directly into arthritic joints can reduce both blood vessel density and arthritis symptoms.

Rheumatoid arthritis is an inflammatory joint disease, resulting from expression of pro-inflammatory and angiogenic cytokines in the synovial space, and the subsequent immune infiltration and new blood vessel growth. Min and his collaborators injected a lentiviral vector containing the gene for endostatin into the diseased joints of a transgenic mouse expressing human tumor necrosis factor (a proinflammatory angiogenic cytokine). Expression of the endostatin gene ameliorated the inflammation and the angiogenic growth, as well as the arthritic symptoms. The authors demonstrate that this is accomplished through the reduction of proinflammatory cytokine expression in the joint, suggesting that endostatin may be an effective therapy for the treatment of rheumatoid arthritis in humans. However, there are still many questions about the mechanism of endostatin that remain to be answered, although this should not necessarily prevent further clinical investigation of this enigmatic molecule.

Other items of interest:

Editorial: 
Politics and AIDS: A Bad Mix
Editor-in-Chief Inder Verma of the Salk Institute reflects on a recent visit to South Africa and the ongoing political - not scientific - battle over the cause and treatment of HIV in a country decimated by the virus.

Review:
Molecular Therapies for Colorectal Cancer Metastatic to the Liver
Joseph Bertino and his collaborators of Memorial Sloan-Kettering Cancer Center review the astounding advances being made in the molecular therapy of not only primary colon cancer tumors, but particularly their metastases.

Articles:
A pair of storage disorder successes

("Correction of the Enzymatic and Functional Deficits in a Model of Pompe Disease Using Adeno-associated Virus Vectors." Fraites, T. J., Jr., et al. (2002). Molecular Therapy 5: 571-578. "Enhanced Secretion and Uptake of Beta-Glucuronidase Improves Adeno-associated Viral-Mediated Gene Therapy of Mucopolysaccharidosis Type VII Mice." Elliger, S. S., et al. (2002). Molecular Therapy 5: 617-626).

Pompe disease and Sly syndrome, two of the several genetic diseases identified as lipopolysaccharide storage disorders, are successfully treated in animal models of the disease, both using adeno-associated virus as the vector of choice.

Others:
An effective cancer vaccine
Optimizing lentivirus for CNS gene delivery

Embargo policy:
Embargo of Molecular Therapy manuscripts applies ONLY to those manuscripts that have not completed the peer-review process. In other words, articles that have been fully accepted for publication may be cited as Molecular Therapy articles: the actual date of publication is irrelevant, as basing an embargo on the date of publication serves the interest of the journal rather than of the science.

Fintan R. Steele, Ph.D.
Editor, Molecular Therapy; Executive Editor, Genomics
Academic Press/Elsevier Science
15 E. 26th St. 15th Floor
New York, NY 10010
646-935-3742 fax
fsteele@acad.com
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The American Society of Gene & Cell Therapy (ASGCT) is a professional non-profit medical and scientific organization dedicated to the understanding, development and application of genetic and cellular therapies and the promotion of professional and public education in the field. For more information on ASGCT, visit its website, www.asgct.org.

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