By Debbie Strickland

Associate Managing Editor

Gene therapy has suffered a few high-profile setbacks this past year, most notably the death of a clinical trial patient at the University of Pennsylvania under the care of James Wilson, director of the Institute for Human Gene Therapy and former president of the American Society of Gene Therapy (ASGT).

Both Wilson and Jeffrey Isner - another pioneer in gene therapy - have received warning letters from the FDA for alleged clinical trial violations. Isner, chief of vascular medicine at St. Elizabeth's Medical Center in Boston, was conducting studies with a gene therapy delivering vascular endothelial growth factor plasmid (VEGF-2) for cardiovascular applications.

These events may have prompted intensified public and FDA scrutiny of such trials, but in the meantime, plenty of products are inching their way down the pipeline. At the 3rd Annual Meeting of the American Society of Gene Therapy in Denver this week, investigators are reporting on preclinical and clinical progress of gene therapies to treat cancer, cardiovascular diseases and a variety of genetic disorders, particularly hemophilia.

Avigen Inc., of Alameda, Calif., reported positive data from a Phase I/II trial of a gene therapy for hemophilia B at ASGT. The company is planning a second trial of the product, Coagulin-B, which uses an adeno-associated virus vector to deliver the gene for Factor IX. The new trial would test safety and effectiveness of infusing Coagulin-B into the liver, which is the normal site of clotting factor production.

Cell Genesys Inc., of Foster City, Calif., and collaborators from the National Institutes of Health also are targeting hemophilia B. Researchers in their collaboration produced therapeutic levels of Factor IX in primate models of hemophilia B following a single administration of a hemophilia gene therapy to the liver using the company's adeno-associated viral delivery system.

GenStar Therapeutics, of San Diego, reported preclinical data on two products - one for hemophilia and one for HIV. The company's hemophilia A gene therapy provided further evidence of a mini-adenoviral vector system's ability to deliver the gene for human Factor VIII at therapeutic levels with no significant toxicity. The HIV vaccine candidate, which uses a genetically modified virus that is incapable of replication, induced an immune response against the virus that destroyed infected cells in laboratory testing.

In other news from the conference:

AVI BioPharma Inc., of Portland, Ore., reported its Neugene antisense drug significantly slowed progression of polycystic kidney disease. Data will be presented this week at the Forefronts in Nephrology Symposium on Gene Therapy in Beaver Creek, Colo., a satellite symposium to the ASGT meeting.

Phogen Ltd., of Cambridge, UK, and Canji Inc., the San Diego-based gene therapy discovery center for the Schering-Plough Research Institute, have demonstrated in a preclinical tumor model that gene therapy with a VP22-p53 fusion protein induces a significantly higher level of tumor cell death than with the tumor-suppressor p53 alone. VP22 is a protein that quickly spreads from cell to cell, and is capable of transporting large proteins (such as p53) in a functional form from the cell in which they are made to neighboring cells, enhancing therapeutic effect.

Targeted Genetics Corp., of Seattle, presented Phase I clinical data for an aerosol formulation of tgAAV-CF, a gene therapy for cystic fibrosis. The product was well-tolerated in 12 patients aged 19 to 41 with mild CF lung disease and achieved broad distribution in the lungs. The company also presented data from its gene therapy program for rheumatoid arthritis, which is using adeno-associated virus vector technology to deliver the DNA sequence encoding tumor necrosis factor receptor-immunoglobulin Fc fusion protein (TNFR:Fc) - Immunex Corp.'s Enbrel - for rheumatoid arthritis and other inflammatory diseases. A single intra-articular (joint) administration of AAV-rTNFR:Fc into both rear ankle joints of arthritic rats resulted in a significant reduction of ankle and hind paw swelling as measured by arthritis index scores. A single intramuscular administration produced a similar effect.

Vical Inc., of San Diego, introduced Vaxfectin, a cationic lipid formulation designed to enhance efficiency of DNA vaccines, at the ASGT meeting. In preclinical testing, Vaxfectin was shown to boost the antibody immune response evoked by naked DNA vaccination as much as 10-fold without reducing cell-mediated response. The company also provided an overview of clinical trials with Allovectin-7, in registration trials for metastatic melanoma, and Levectin, in late Phase II trials for metastatic kidney cancer.