© 1998 by Oxford University Press
No one liked the term "phase zero" to describe the first proposal -- still under development -- to attempt gene therapy in unborn fetuses with genetic diseases that either cause prenatal death or lifelong disability. Much more apt, participants in a federal advisory panel agreed, is to call these attempts -- should they move ahead -- traditional phase I studies gathering information about safety.
Safety, however, is just one of the unknowns surrounding the milestone "preproposal," put forth as the first step in public discussions by W. French Anderson, M.D., of the University of Southern California, and Esmail Zanjani, Ph.D., of the University of Nevada, at a recent 2-day hearing before the Recombinant DNA Advisory Committee.
The RAC, which advises National Institutes of Health Director Harold Varmus, M.D., on gene therapy, listened as even the investigators acknowledged that an attempt to correct genetic defects in utero is an idea fraught with emotional, ethical, and scientific hurdles. Not the least of the problems, said Anderson, is how much blood volume can be safely removed from a developing fetus that weighs only 250 grams. Also, at issue, is what percentage of stem cells need to be corrected in order for a fetus with a genetic disease to derive more benefit than harm from treatment.
Under consideration for now are two diseases: adenosine deaminase (ADA) deficiency, a crippling immune disorder, which was the first disease ever treated with gene therapy; and alpha thalassemia, a blood disorder that is often fatal to fetuses prior to birth.
Which of these diseases might be the best choice for an initial genetic therapy attempt in the womb is undecided and raises still more questions, according to RAC members. Central to the debate is whether it would be better to treat a disease in which backup therapies exist as they do for ADA, or to proceed with one -- alpha thalassemia -- where parents might choose in utero gene therapy out of desperation because of a lack of other alternatives.
At this early stage, said RAC member Louise Markert, M.D., Ph.D., Duke University Medical Center, Durham, N.C., there is agreement that more data are needed on safety and efficacy, as well as information on possible inadvertent alterations in a fetus's germline cells -- outlawed under federal regulations.
In January next year, the RAC will hold a Gene Therapy Policy Conference on the issue. "This has been a good dialogue between investigators and the RAC as to what is needed before such a protocol is fully developed," summed up Claudia Mickelson, Ph.D., Massachusetts Institute of Technology, Cambridge, and the RAC chairman.
-- Susan Jenks
Researchers Seek Guidance on "Preproposal" for In Utero Gene Therapy
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