The United States Food and Drug Administration (FDA) held a meeting of the Xenotransplantation Subcommittee on June 3-4, 1999 in order to seek expert and public input into the creation of a final regulatory framework for xenotransplantation. As well as members of the FDA, many of the top experts in related fields were present, representing disciplines such as:
 

The FDA did an excellent job of convening a panel of experts whose input will shape xenotransplantation regulations in the United States. My impression was that FDA was genuinely seeking guidance, and was not pushing its own agenda. Unlike many European governments who quietly wrote their own regulations with minimal input from outsiders, the FDA encouraged a democratic and science-based process.

The Bottom Line...

In this report, I would like to start at the end. For those of us whose health and even survival may depend on a reasonable regulatory framework for xenotransplantation, the outcome could not have been better! On the second day of the conference, Dr. Hugh Auchincloss - Chair of the FDA Xenotransplantation Subcommittee - told me in clear and definite terms that:

• the FDA will allow clinical trials of cellular xenotransplantation to proceed; and
• the discussion is now focussed on whole organ xenotransplantation, and whether it offers sufficient benefit today to approve clinical trials. 

The Hard Facts...

Speaker after speaker presented hard facts supporting the position that the much-feared Pig Endogenous Retrovirus (PERV) was not capable of infecting humans. Some of the highlights:

• Dr Carolyn Wilson of the FDA presented the FDA perspective. She described how the FDA placed a hold on the 10 xenotransplantation clinical trials then approved in October 1997 until each researcher could demonstrate that he or she had sufficiently sensitive assays to detect low levels of PERV infection. Of the 10 trials, 6 were restarted when the FDA was satisfied with the assays being used.  In these trials, of 29 recipients who received pig cells, 0/29 tested positive for PERV infection.

 
• Dr. Walid Heneine of the Centers for Disease Control (CDC) presented data on Porcine Factor 8 (PF8) sold under the trade name of Hyate C. PF8 is an agent derived from pigs and used by hemophiliacs who are unable to tolerate human clotting factor. A large number of batches of PF8 were tested for PERV, and 100% were found to be PERV-positive (as PERV is part of a pig's DNA, it is present from birth even without infectious exposure). However, of 88 recipients who received transfusions of  PF8, 0/88 were found to be PERV-positive. These transfusions present an ideal opportunity for PERV infection, and yet the retrovirus once again proved incapable of infecting human cells. The tragic irony here is that many of the hemophiliacs who received human clotting factor contracted AIDS and hepatitis, demonstrating once again that material derived from sterile, purpose-bred pigs is safer than material from humans.

 
• Dr Walid Heneine of CDC also presented data on people receiving pig islet cells. Each received 200,000 to 2,000,000 islets, and all had levels of porcine C-peptide, indicating that the islets were surviving and secreting pig insulin. Of the 10 recipients tested, 0/10 were PERV-positive (both PCR and serological antibody assays). In one recipient, there was a weak positive for PERV infection, but when tested 7 days later, the results were PERV-negative. PCR is very susceptible to false positives as a result of contamination or microchimerism, and so it is sometimes necessary to test more than once.

 
• Dr Gillian Langford of Imutran Limited presented the results of pig organs transplanted into non-human primates (monkeys and baboons). All these animals were heavily immunosuppressed, and so were relatively incapable of fighting any infection. Of 100 monkeys and baboons that received pig organs, 0/100 showed PERV infection in multiple tissues tested. The tests looked for PERV viral fragments amplified through Polymerase Chain Reaction (PCR) as well PERV antibodies. Pig cells were detected in all tissue tested, indicating either microchimerism or the release of cells during rejection. Once again, the conditions for infection were ideal, and none occurred.

 
• Dr. Zorina Pitkin of Circe Biomedical presented the results of assays on people whose blood was circulated through pig liver cells in Circe's HepatAssist liver support system. Again, all recipients tested negative for PERV infection.

 
• Dr. Jonathan Dinsmore of Diacrin, Inc. presented data from patients who received pig neural cells as a treatment for Parkinson's disease, Huntington's disease, and focal epilepsy. Of the 33 patients tested, 0/33 were PERV-positive. These patients received approximately 12,000,000 cells each.  Half were immunosuppressed, and half underwent antibody depletion prior to transplant.

 
• Dr. John Logan of Nextran, Inc. presented results from humans and baboons who received cell xenografts from transgenic pigs. All recipients showed a powerful alpha-Gal response, indicating the presence of pig cells, but no PERV infection.

 
• Dr. Khazil Paradis of Imutran Limited described the extensive testing of humans who have received various pig cells over the past decade. This testing was undertaken collaboratively by Imutran and the CDC. Dr. Paradis was only able to describe the methodology of this investigation, and not its results as publication is planned for later this summer. However, if I were a betting man, I would place a huge bet on a PERV-negative outcome.

• All pigs are positive for PERV
• All humans who have received pig tissue are negative for PERV
• All non human primates who have received pig tissue are negative for PERV
• All humans who received Pig Factor 8 as a clotting agent are negative for PERV
• Many recipients were heavily immunosuppressed, presenting very little defense against any infection

Dr. Harold Vanderpool of the University of Texas Institute for Medical Humanities presented a perspective on the ethic of xenotransplantation that was refreshingly different from what I have heard here in Canada. Dr. Vanderpool described the ethical considerations as having three equal parts:

• Benefit - Is it reasonable to expect that xenotransplantation will potentially relieve human suffering and prolong life?
• Risk - Is is reasonable to expect that xenotransplantation is safe for the patient, and more importantly, for society at large?
• Justice - Do other groups enjoy access to medical procedures that are of similar or greater cost and risk ?

Anti-CD40-Ligand a.k.a. Anti-CD154...

Dr. David K. C. Cooper of the Transplantation Biology Research Center at Harvard Medical School presented some fascinating data on xenografts of pig whole organs into primates. Dr. Cooper pointed out that in 1991 there were 4 reports on pig-to-primate transplants. In 1999, there have been 150 reports in the first six months. Many researchers are seeing enough promise in this field to focus their careers on it. 

Dr. Cooper described the stages of rejection that must be overcome before a whole xeno-organ will be accepted by its host. The rejection process seems to follow 4 stages: hyperacute rejection (HAR), acute vascular rejection (AVR), cell-mediated rejection, and chronic rejection. In the case of islets, HAR does not seem to happen, likely because alpha-Gal is not present on islet cells. AVR likewise does not happen to islets, as they are not vascularized (grafted to blood vessels). Without immune protection, the remaining two stages of rejection will destroy islets just like any other transplanted tissue. 

Dr Cooper discussed the work of Drs. David Harlan and Allan Kirk of the U.S. Naval Medical Research Institute in which monkeys have accepted a mismatched kidney allograft for up to 1.5 years without ongoing immunosuppression. During the first month, these monkeys received a course of Anti-CD40-Ligand (now known as Anti-CD154) and no immunosuppression thereafter. Not only have the kidneys worked well, but the monkeys have avoided the adverse effects normally associated with immunosuppression.

The next challenge is to use Anti-CD154 to prevent rejection of pig organs in primates, especially humans. Although some increase in the acceptance period was observed, Dr. Cooper speculated that Anti-CD154 may have to be combined with transgenic donors and bone marrow transplantation before it can induce xenotolerance.

Other Items...

This summary is a quick overview of the FDA Xenotransplantation Subcommittee meeting, with the items of interest to islet xenotransplantation being emphasized. There were many interesting presenters, and dozens of excellent questions and discussions. 

All in all it was a watershed event!
 

Participants at the Meeting...
 

Mary Groesch, Ph.D. Senior Science Policy Analyst Office of Science Policy Office of the Director National Institutes of Health Building 1, Room 218 Bethesda, MD 20892-0166