By Lisa Seachrist

Washington Editor

ROCKVILLE, Md. — Nearly a decade ago, when Baby Fae received a baboon heart transplant, xenotransplantation was a new and unregulated technology just testing the clinical waters.

Baby Fae's transplant failed. But now, with the advent of molecular techniques and gene therapy, the clinical community stands at the dawn of a new age in transplantation science, where genetically modified pig organs could offer hope to thousands of patients in need of liver and kidney transplants or afflicted with Parkinson's or Huntington's disease.

However, that promise was called into question earlier this year when researchers at the Institute for Cancer Research in London announced that endogenous retroviruses in pig tissues can infect human cells in culture. The finding raises the possibility that these apparently ubiquitous viruses could infect transplant recipients and, perhaps, be transmitted to others through a number of routes.

In light of this dilemma, the FDA has chosen to place a clinical hold on all porcine xenotransplants. In order to evaluate how to regulate this new technology, the agency convened a special xenotransplantation subcommittee of the Biological Response Modifiers Advisory Committee Wednesday.

"If we over-regulate unnecessarily, we slow down the progress of this technology for patients," said Mary Pendergast, deputy commissioner at the FDA. "If the risks are too great to let the technology go forward, then we must have the courage to say no."

Much of the difficulty in determining the appropriate level of regulation comes from the fact that not much is known about the porcine endogenous retroviruses (PERVs) or their ability to cause disease in humans. In pigs, the virus lays quiescent and doesn't cause disease.

Most viruses are limited in the number of hosts which they can infect. Robin Weiss, of the Institute for Cancer Research, reported in Nature Medicine in March that these endogenous viruses which are incorporated into the genome of all pigs could infect human cell cultures. The infection, however, occurred with some difficulty.

Approximately 100 patients have received either fetal pig brain tissue to treat Huntington's or Parkinson's diseases or have been exposed to pig liver cells in a plasma transfer system similar to dialysis. To date, none of these patients has tested positive for PERVs in their peripheral blood cells using PCR and reverse transcription PCR. However, no antibody test for PERVs exists and many ubiquitous human viruses like Epstein-Barr virus fail to show up in DNA tests, but the infection can be confirmed with an antibody test.

"I think the antibody tests are going to be very important — they are coming along, but it will take time," said Weiss. "There is something positive to do there in order to understand the likelihood of infection."

In the absence of assurance that PERVs aren't infecting porcine tissue recipients, several panel members were unwilling to suggest that the clinical trials on these materials should proceed.

Infection Risk Weighed Against Organ Demand

"I think it is possible that all of these people are infected, but we don't know the answer to that," said panel member Ronald Desrosier, professor of Microbiology and Molecular Genetics at Harvard Medical School. "In the absence of any further information, I would not transplant tissue that carries a known infectious agent. We need much more preclinical information."

The problem with such a position is that there is as yet no animal model that can give researchers an idea about the pathogenicity of an infection with a PERV. In addition, the need for transplant organs motivated most panel members to consider lifting the clinical hold.

"There are 60,000 people who are awaiting donor organs," said panel member William Lawrence, director of patient affairs at the United Network for Organ Sharing. "Ten people are going to die as we discuss this issue today."

Panel chairman Hugh Auchincloss, associate professor of surgery at Harvard Medical School agreed, "I do not want us to deny something that is helpful when we aren't sure there is a danger. There isn't any data so we've moved into the realm of opinion."

However, given the fact that there is a potential public health issue involved, transplant recipient Antonio Benedi, vice president of the Transplant Recipient International Organization, noted that he would have not agreed to a transplant if that meant there was a chance that he would infect his loved ones with a virus that had potential dangers that weren't known.

"I think we are in the chicken and the egg syndrome—at what stage do you let things go forward?" asked Kathryn Zoon, director of the Center for Biologics Evaluation and Research. "If it were only involving the individual it would be a fairly straight forward decision. Do you stop things while you wait to get that data or do you move forward?"

The panel, in general, felt that public health concerns could be examined with animal studies and evaluation of patients already treated while some clinical trials proceeded. *