This is the press release for the June 2002 issue of Molecular Therapy, the journal of the American Society of Gene Therapy. Academic Press, an imprint of Elsevier Science, publishes Molecular Therapy monthly.

Please credit Molecular Therapy as the source of this information. The print version of this issue will be available at the Annual Meeting of the American Society of Gene Therapy in Boston, June 5-9, 2002. It is currently available online at www.academicpress.com/moltherapy. The embargoed abstracts from the upcoming meeting are available at http://www.academicpress.com/ASGT.

The embargo for the June issue articles is lifted upon your receipt of this message. Embargo of manuscripts at Molecular Therapy applies only to articles that have not completed the review process, i.e., only articles accepted for publication may be cited. PDF files of the below-described manuscripts (with author contact information) are available to direct recipients of this message on request and for reporting purposes only. All questions should be directed to the editor (see below).

On the cover: Not all reporters are good

(Detrait, E. R., et al.(2002). Reporter Gene Transfer Induces Apoptosis in Primary Cortical Neurons. Molecular Therapy 5: 723-730.)

Despite its complexity, the nervous system is likely to be the site of some of the earliest gene therapy successes, with studies underway in Parkinson's disease, Alzheimer's disease, and other disorders and diseases. Much of this progress is a result of the ready availability of "reporter genes," i.e., genes that encode proteins that can be easily visualized. Common ones include green fluorescent protein (GFP), firefly luciferase, or E. coli beta-galactosidase. The aesthetically stunning photographs of central nervous system neurons "lit up" by such reporter genes are well known.

But in gene therapy, beauty can extract a price. A group of researchers at the University of Rochester (New York) report that commonly used reporter genes can cause significant toxicity to nerve cells. Indeed, if one wants to learn if gene transfer of a therapeutic gene is successful, imaging the treated neurons by means of an accompanying reporter gene would suggest that the therapeutic gene had little or no neuroprotective effect. In fact, it may have, but it would not be seen because of the neurotoxicity of the reporter gene.

Although a bit disheartening, such work is critical in underscoring the need for careful design of gene expression vectors.

Beating breast cancer metastasis

(Shi, H. Y., et al. (2002). Inhibition of Breast Tumor Progression by Systemic Delivery of the Maspin Gene in a Syngeneic Tumor Model. Molecular Therapy 5: 501-508.)

The development of any successful gene therapy requires not only a therapeutic gene, but an effective drug delivery system. In addition, a good animal model is critical for most applications, particularly in cancer gene therapy. In this issue, a group of Baylor College of Medicine researchers led by Ming Zhang present both a good animal model and a good delivery system for inhibiting both primary tumor growth and metastases of breast cancer.

In creating the animal model, the researchers implanted highly invasive and metastatic tumor cells into mouse mammalian tissue. After determining that the cells behaved "properly" (i.e., caused tumors and metastasized readily), they treated these mice systemically with a nonviral vector carrying the gene encoding "maspin," a protein that likely plays a role in tumor suppression. The treated mice had a significant reduction in tumor growth and spread. Even more exciting, the vector chosen had very limited toxicity of its own, as did high expression of the maspin gene. The combination of the strong animal model as well as the safety and efficacy of the treatment in this case suggests that this can serve as an effective therapy for human breast cancer.

More than oxygen exchange

(Li, C., et al. (2002). Adenovirus-Transduced Lung as a Portal for Delivering alpha-Galactosidase A into Systemic Circulation for Fabry Disease. Molecular Therapy 5: 745-754.)

Most gene therapy research that seeks to provide a therapeutic molecule systemically has focused on the liver or skeletal muscle as a "depot" for protein production from a transgene, e.g., clotting factors in hemophilia. But other organs that are intimately involved with the circulation could serve as well. Seng Cheng and his collaborators at Genzyme (Framingham, MA) demonstrate that the lungs can provide the body with more than air.

Using mice that model Fabry disease (a devastating human phospholipid storage disorder that affects a variety of tissues), the researchers transferred the gene encoding the normal protein in a recombinant adenovirus vector to the animals' lungs. The treated lungs made the therapeutic protein and, even more exciting, the protein successfully crossed the "air/blood barrier" and was taken up by distant organs, reducing the abnormal phospholipid storage dramatically.

Compared with liver or even skeletal muscle, treatment of lung by gene therapy is relatively noninvasive. If such results as those presented by Li et al. continue to be seen in animal trials and can be demonstrated in humans, inhalation gene therapy may become a standard clinical protocol.

Other items of interest:

Editorial:
Do not ban therapeutic cloning

Editor-in-Chief Inder Verma of the Salk Institute argues that a blanket ban on "cloning" will have chilling effects on scientific progress.

Issue:
Ad in or Ad out?

A new section opens this month, written by professional science writers, and considers issues of debate or immediate consequence in the growing field of gene therapy. In this first installment, Barbara Nasto reports on the growing concerns about the ongoing use of adenovirus for systemic delivery, particularly in light of the data that have come out of the death at the University of Pennsylvania.
(Reporters and Editors: We are soliciting both writers and ideas for this section. If interested, contact the Editor (below).)

Review:
Sturm und Drang over Suicidal Lymphocytes

Michel Sadelain and Isabelle Riviere of Memorial Sloan-Kettering Cancer Center consider the true risks of random insertion of retrovirus vectors, following a recent short paper in Science describing the development of leukemia in mice treated with such vectors.


Clinical Trial:

Although antiretroviral treatment has brought new hope to HIV patients, the treatments are expensive and long-term, perhaps for life. The latter is due to "viral reservoirs" where the virus lurks in relative quiet, waiting for a chance to replicate again. Several gene therapy approaches, aimed at stimulating the cellular immune system to wipe out HIV-infected cells, have begun, including the phase II trial of one such approach detailed in this issue.


Meeting Report:

David Bodine (NIH) and David Emery (University of Washington) recount the positive spirit and emerging breakthroughs featured at the recent Annual Meeting on Hematopoietic Stem Cell Gene Therapy.

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
http://authors.elsevier.com/JournalDetail.html?PubID=622922&Precis=DESC
http://www.academicpress.com/genomics

 ###