By Lisa Seachrist

Washington Editor

BETHESDA, Md. - Correcting inherited misspellings of DNA and ending suffering by curing diseases at their root cause remain the promise of gene therapy.

That promise has led researchers to contemplate correcting those genes in utero, before an affected individual has any chance to suffer from a genetic disease at all and at a time when gene transfer may be more readily accomplished. But, as researchers explore such possibilities in animal models, they are facing difficult ethical issues.

"One of the most difficult scientific and ethical issues we face is the adventitious insertion of new genetic material into the germline," Robertson Parkman, professor of pediatrics and microbiology at the University of Southern California Medical School in Los Angeles, told participants at the Recombinant DNA Advisory Committee's Third Gene Therapy Policy Conference. "The effects of such an event would have reverberations for society, not just the individual patient, and our current framework for assessing risks and benefits doesn't account for societal risks."

In fact, the unintended side effects of prenatal gene therapy may require that researchers develop an entirely new paradigm for moving in utero gene transfer experiments from preclinical animal testing to actual clinical trials. As Jeremy Sugarman, associate professor of medicine and philosophy at Duke University Medical Center in Durham, N.C., noted, "It's not an ethics softball."

Sugarman pointed out that the medical research community is quite adept in conducting Phase I clinical tests, but much less thought has been put into identifying the ethics involved in deciding when a therapy is ready to move from animal testing to humans. Because prenatal gene therapy means experimenting on an individual who has yet to be born and could result in accidental alterations of the germline, establishing the correct process to move the science into human applications is vital, Sugarman said.

"Really, what we are talking about is moving from the bench to the barn to the bedside," Sugarman said. "In determining whether to make the leap from animals to humans there are several considerations evaluated for Phase I clinical trials that are necessary but not sufficient."

Those considerations include the possibility of benefit, safety, experimental design and informed consent. As Sugarman sees it, the benefit is measured not for the individual in a Phase I clinical study, but as a measure of what is the benefit of the knowledge for society. Safety issues, on the other hand, are discussed in terms of the individual participating in the study. Experimental design issues are examined with an eye toward merit of the information. Informed consent is limited to the individual.

"We really need to rethink the informed consent process as we look at intergenerational research," Sugarman said. "When experimenting on children, you aren't looking for informed consent from the children, but you are asking for permission from the parents. Children born following an in utero gene therapy attempt will require long-term follow-up, and should in utero gene transfer result in a germline alteration, we are looking at future generations as well. We really don't know about how a person gives informed consent for future generations."

In addition, safety issues for the mother and the fetus may be at odds, muddying how to assess the safety of a given protocol.

And, Sugarman noted, a Phase I trial is a test of toxicity. Current regulations for testing gene therapy have what he calls "an implication of therapeutic benefit. It's unclear how to balance those competing claims."

The problems of adventitious germline alteration are likely to present some of the most difficult issues in deciding whether a prenatal gene therapy can safely and ethically move to clinical testing. Scientists have traditionally set germline alteration as a boundary they wouldn't cross. However, animal experiments show that introducing gene transfer vectors in utero will result in a small amount of gene transfer to gonadal tissue, which could result in a germline alteration.

"All therapies have potential side effects and gene therapy is no different," Parkman said. "Should adventitious germline alterations be dealt with as side effect or is it quantitatively and qualitatively different? We need to have those discussions on a societal level."

Sugarman agreed and proposed that in funding research into prenatal gene therapy, the National Institutes of Health also should consider funding ethics research into these questions. n