By Vicki Brower

Special To BioWorld Today

BOSTON — After 18 years of experiments with but few concrete successes, gene therapy is being reconceptualized "as an alternative way to deliver drugs [rather than as a way] to treat genetic diseases by 'fixing' nonfunctioning genes," said James Wilson, one of the pioneers of the science.

"Because of our experience in over 200 gene therapy protocols to date with only very limited successes, our concept of gene therapy has evolved to changing cell function in less direct ways than modifying a malfunctioning gene," said Wilson, director of the Institute for Human Gene Therapy at the University of Pennsylvania, in Philadelphia.

It has been necessary to go back to the drawing board, he added, and do more basic research on vectors as well as diseases. Newer indications for which gene therapy is being used as a drug delivery system include cardiovascular (restenosis) diseases and hemophilia.

Proof of principle, Wilson observed, could come in the next few years and would be most unambiguous in inherited diseases, with initial success expected in the cardiovascular area — in which interest has been "exploding."

Wilson's update on the progress of gene therapy came during a two-day conference this month at the Massachusetts Institute of Technology, in Cambridge, sponsored by MIT's Whitehead Institute for Biomedical Research; the George Washington University Medical Center, of Washington; and the American Society of Law, Medicine and Ethics, of Boston. The meetings focused on the "Human Genome Project: Science, Law, and Social Change in the 21st Century."

In recent years scientists have moved away from gene therapy's first sights — rare, single-gene defect diseases such as cystic fibrosis, sickle cell anemia and muscular dystrophy — which have proven to be more difficult to cure than anticipated due to a number of crucial roadblocks.

"Of primary importance," Wilson explained, "is finding the right gene delivery vehicle, or vector." Two other crucial issues are getting the desired gene into the proper site without rejection and the regulation of gene expression, what Wilson called "a molecular rheostat."

Some gene therapy failures have come about due to first-generation viral vectors that have not been sufficiently attenuated and hence proved to be too immunogeneic, or not long-lasting enough to continue viral expression.

Ethical Concerns Also Loom

Still other problems in gene therapy have come in the form of pressing ethical issues, said Leroy Walters, director of the Kennedy Institute of Ethics at Georgetown University, in Washington.

The consent process, especially for Phase I gene therapy trials, has often been problematic and has seemed to promise patients benefit when it is unlikely, Walters said. Because little tangible success has been achieved, but public expectation has been high, he suggested using the term "gene transfer" rather than "therapy."

Language in consent forms also has been unclear, Walters said, with the cost of medical treatment, in the event of adverse reactions or injury, not guaranteed.

Since the Recombinant DNA Advisory Committee (RAC) was disbanded, Walters added, oversight of gene therapy trials has been spotty and uneven, with little true protection for research subjects.

Both Walters and Wilson noted public discourse about gene therapy during RAC's tenure was largely responsible for forming public opinion and moving the field forward. Moreover, the experts said gene therapy reviews, conducted in private at the FDA and at the local level by institutional review boards, have produced conflicts of interest.

"We ought to re-examine where it is best that public review of these trials should take place," Walters said.

He suggested more oversight could occur if gene therapy review was conducted by the Department of Health and Human Services or by a newly created independent body for protection of human subjects — "similar to what we have with the Federal Communication Commission [FCC]."

Walters said, "The irony is that now there is more careful attention given to the airwaves than human gene therapy trials." *