ASGCT Press Release

This is the press release for the April 1, 2002, issue of Molecular Therapy (Volume 5, 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/Elsevier Science (USA). 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).

On the cover: Endostatin Enigma

It is not often that scientific journals publish negative results. However, if the experiments are well-performed and have an immediate and direct relation to medical research, such data are important to present. In this issue of Molecular Therapy, two papers raise a series of troubling questions about the use of endostatin, a highly trumpeted antiangiogenic molecule, in cancer treatment.

Philippe Leboulch of Harvard and the Massachusetts Institute of Technology and Connie Eaves of the Terry Fox Laboratory in Vancouver led two groups of researchers who rigorously examined gene therapy approaches to providing efficacious levels of endostatin in mouse models of different forms of cancer. Despite attaining high circulating levels of functional endostatin through the transduction of hematopoietic stem cells with the gene, the researchers did not see any significant anti-tumor effects. Furthermore, the researchers were unable to replicate previously published work that suggested efficacy in mouse models. Given that endostatin clinical trials in humans are underway based in large part on these prior publications, these articles highlight not only the question of adequate preclinical models for testing this molecule in humans, but also reveal the difficult questions that face any research initiative that seeks to move from the lab bench to the clinic.

A commentary explaining the position of the journal in publishing these papers and examining some of the questions raised accompanies these papers in this issue.

Pawliuk, R., et al. (2002). Continuous intravascular secretion of endostatin in mice from transduced hematopoietic stem cells. Mol. Ther. 5:345-351.

Eisterer, W., et al. (2002). Unfulfilled promise of endostatin in a gene therapy-xenotransplant model of human acute lymhocytic leukemia. Mol. Ther. 5: 352-359.

Steele, F. R. (2002). Can "Negative" Be Positive? (Commentary). Mol. Ther. 5: 338-339.

Targeting Cystic Fibrosis I: Respiratory treatment

Although there have been many gene therapy-related attempts to treat cystic fibrosis, most have fallen short due to a combination of the pathophysiology of the disease itself and strong immune reactions to the vector used to transfer the therapeutic gene. However, the basic premise of replacing the faulty protein (CFTR) through gene transfer remains the goal, and many researchers are pursuing alternative strategies. 

In this issue of Molecular Therapy, a group led by Pamela B. Davis of the Case Western Reserve University in Cleveland describes one such novel approach that shows great promise for treating the respiratory manifestations of cystic fibrosis. They take advantage of the basic biology of cell surface receptors to construct a "receptor-directed molecular conjugate" within which is packaged DNA that encodes the CFTR gene.

Choosing a conjugate that targets the serpin-enzyme complex receptor, they show that they can get a degree of restored normal physiology in vivo in airway epithelial cells treated with this therapeutic approach. Although further toxicology and safety studies of these compounds are required, the approach shows significant potential for the eventual clinical treatment of cystic fibrosis.

Ziady, A.-G., et al. (2002). Functional evidence of CFTR gene transfer in nasal epithelium of cystic fibrosis mice in vivo following luminal application of DNA complexes targeted to the serpin-enzyme complex receptor. Mol. Ther. 5: 413?419.

Targeting Cystic Fibrosis II: Gastroenterological treatment

Cystic fibrosis, although popularly thought to be a disease of the respiratory tract, affects many other bodily systems. In particular, many adult CF patients suffer liver (specifically biliary) and pancreatic complications from the disease. Providing a correct gene replacement to these tissues is a difficult undertaking. However, in this issue a group of researchers led by Charles Coutelle of the Imperial College School of Medicine in London describe an approach that takes advantage of the normal cell physiology of these tissues to target the therapeutic gene, i.e., CFTR.

In addition to expression of CFTR, biliary and pancreatic epithelia cells express the receptor for secretin, a digestive hormone. By coupling secretin to the CFTR-containing delivery vector (in this case a nonviral carrier molecule), the researchers show that treatment of cells expressing the secretin receptor resulted in significantly higher transfer of the corrective gene. They also test this concept by linking secretin to an adenoviral vector, and show enhanced specificity and transfer to secretin receptor-expressing cells. These results show significant clinical potential for this approach, which may overcome some of the hurdles associated with delivery to specific tissues from a systemic treatment.

McKay, T., et al. (2002). Secretin-mediated gene delivery, a specific targeting mechanism with potential for treatment of biliary and pancreatic disease in cystic fibrosis. Mol. Ther. 5: 447-454.

Other items of interest:

Editorial: Censorship of Scientific Publications: A Bad Idea?
Editor-in-Chief Inder Verma considers the recent actions by the US Administration in response to last year's bioterrorism attacks, and concludes that asking scientific publications to limit or "censor" papers that could be misused is going too far.

History: Evolution of Adenoviruses as Gene Therapy Vectors.
This installment of the ongoing series on the "History of Gene Therapy" recounts the discovery and subsequent triumphs and travails of the most studies and widely used gene therapy vector to date. The authors are Jayanta Roy-Chowdhury and Marshall S. Horwitz of the Albert Einstein College of Medicine in New York.

Article: HIV and Stem Cells
To take full advantage of stem cells, it will be necessary to have effective ways to shuttle genetic information into the cells without disrupting their potential. An article by Jiing-Kuan Yee and his colleagues at the Beckman Research Institute describes the optimization of HIV-derived vectors for efficient gene delivery into human hematopoietic cells.

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). It is NOT our policy to hold an accepted article secret until the journal is published, as we  believe that this is not in the interest of scientific progress. It is just as important to note that manuscripts still undergoing peer-review should NOT be reported as being published in Molecular Therapy.

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
212-592-1023 phone
646-935-3742 fax
fsteele@acad.com
http://authors.elsevier.com/JournalDetail.html?PubID=622922&Precis=DESC

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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