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Cloning Pigs And Drug Discovery Among "hot" Topics Discussed At International Congress Of The Transplantation Society

August 23, 2002

New developments in the areas of cloning and animal-to-human transplantation, and in drug discovery and transplant tolerance - the acceptance of the graft without the need for drugs - will have the most impact on transplant availability and outcomes, said researchers today who spoke at the International Congress of The Transplantation Society in a session aptly called "What's New and Hot in Transplantation."
The congress, being held at the Westin Diplomat Resort and Spa in Hollywood, Fla., began on Sunday and concludes this Friday.

Xenotransplantation, or cross-species transplantation, is viewed as one answer to the critical shortage of human organs for transplantation. Because the immune system barriers are so great between humans and animals, the field has been dominated by small and incremental developments. But last week's news of the world's first cloned double "knockout" pigs represents a major boost to the field.

"This could well prove the biggest advance in xenotransplantation research to date," remarked Dr. David K.C. Cooper, associate professor of surgery at Harvard Medical School and head, Xenotransplantation Group, Transplantation Biology Research Center, Massachusetts General Hospital. "It is likely, however, that this will not provide the entire answer, and that further gene 'knockout' procedures may be necessary. Nevertheless, a big step forward at this stage would be greatly encouraging to researchers, and would indicate that the organ shortage will be resolved by the use of pig organs within the foreseeable future."

Somatic nuclear transfer, or cloning, of pigs offers "the most radical and promising strategy" for creating pigs that lack the enzyme responsible for hyper-acute rejection, reported Dr. Alan Colman, one of the creators of Dolly, the first animal cloned from an adult cell, at today's congress. Formerly with PPL Therapeutics, PLC, where the work with the pigs was performed, Dr. Colman is now with ES Cell International, Pte., Ltd. in Singapore.

Four cloned double "knockout" pigs were born at PPL Therapeutics, Inc., in Blacksburg, Va., on July 25. Each lacked both copies of the gene responsible for making the enzyme alpha1, 3 galactosyl transferase, a feat that could bring in the next generation of organ donors, making animal-to-human transplantation feasible. Without the enzyme, which adds a sugar to the surface of cells that the human immune system immediately recognizes as being foreign, hyper-acute rejection is unlikely.
Given the current pace of research, when can human trials be anticipated? Australian researcher Dr. Anthony J.F. d'Apice of St. Vincent`s Hospital in Fitzroy, Australia, and president-elect of the International Xenotransplantation Association (IXA), commented that when "knockout" pigs of both sexes are generated that are viable and normal, and survival of grafts extend beyond the current barrier of six to 12 weeks, "human clinical trials would be justified."

Added Dr. Cooper, immediate past president of IXA, a section of The Transplantation Society, after cellular xenotransplantation, "It is likely that the first clinical trials will be of pig islet transplantation in patients with diabetes. The first organs transplanted will likely be the kidney or the heart since we have evidence that these organs will function well in the human body environment. Because of the role of the liver in the manufacture of hundreds of different proteins, many of which are likely to be slightly different in the pig than in the human, trials of pig liver transplantation are likely to be delayed."
In the areas of drug development and transplant tolerance, some of the predictions for future developments discussed in the "What's Hot" session were:
? New research combined with the technological revolution of drug discovery and development, indicate new small or large molecular weight compounds will be designed to regulate immune responses far more specifically and effectively than ever before, reported Dr. Randall E. Morris, head of transplantation and immunology research at Novartis Pharmaceuticals, AG, on leave from Stanford University School of Medicine, where he is professor of cardiothoracic surgery. Newly discovered drugs, some which currently are in development, are likely to have a great impact on the success of achieving transplant tolerance as well. "While drug-free tolerance regimens remain the ideal, current and future advances in immunosuppression will hold all drug-free tolerance regimens-especially for solid organ recipients-to increasingly higher standards of long-term efficacy, safety and logistical feasibility," he told congress participants.

? Genomics, the science of identifying and processing DNA sequences, will play an increasingly important role in the quest to achieve tolerance. Dr. Vicki Seyfert-Margolis, executive director of the Tolerance Assay Group at the Immune Tolerance Network, said small-scale gene expression profiling has led to the identification of genes that appear to be stimulated when acute rejection occurs following kidney transplantation. "Application of global gene and/or protein expression profiling in transplantation offers the opportunity to identify new surrogate markers for monitoring the effect on cell function of certain drugs and immune response following transplantation," she explained.

? With appropriate timing and dosage of immunosuppression, tolerance is more likely to result, says Dr. Thomas E. Starzl, professor of surgery at the University of Pittsburgh School of Medicine. A new strategy, whose origins go back to clinical experience of 40 years ago, seeks to safeguard the steps necessary for tolerance to occur. Instead of the standard approach of giving patients high doses of immunosuppression as soon as the organ is transplanted, the strategy involves giving a one-time dose of a drug to deplete recipient T cells just hours before transplantation - before the antigen is introduced - and then giving lower-than-usual doses of just one anti-rejection drug beginning one day after transplantation. Nine living donor-kidney transplant patients transplanted 40 years ago were treated in a similar fashion. Seven have been drug-free, one for as long as 38 years.

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