Genetically-engineered pig orthotopic (life-supporting) heart transplantation (OHTx) in baboons: establishing consistent graft survival and overcoming rapid post-Tx organ growth

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GENETICALLY-ENGINEERED PIG ORGAN TRANSPLANTATION IN BABOONS: IMMUNOLOGICAL AND FUNCTIONAL STUDIES PROJECT 3: Genetically-engineered pig orthotopic (life-supporting) heart transplantation (Tx) in baboons: establishing consistent xenograft survival and overcoming rapid post-Tx organ growth (PI: Muhammad Mohiuddin). SUMMARY/ABSTRACT The field of xenotransplantation has made significant progress in the last few years. However, successful life-supporting (orthotopic) pig heart transplantation (OHTx) in nonhuman primates is currently limited by two major problems – (i) immediate graft failure from a poorly-understood, non-immunologic cause (known as `peri- operative cardiac xenograft dysfunction' or `PCXD'), and (ii) rapid growth of the heart in the first few post-Tx months, potentially resulting in cardiac compression and dysfunction. We propose investigating and resolving these two problems. (i) We hypothesize that PCXD is associated with impaired mitochondrial function that results from inadequate myocardial preservation during OHTx and low post-Tx triiodothyronine (T3) levels. We shall use a novel system of preservation (the `Steen' system) and combine this with T3 therapy in the immediate post-Tx period. Our detailed studies on mitochondrial function will throw light on the mechanisms involved in PCXD. We have already carried out preliminary testing of the Steen system, with encouraging results, and have confirmed that T3 levels remain grossly subnormal during the first few weeks after pig OHTx in baboons. (ii) We hypothesize that excessive growth of the pig cardiac xenograft will be prevented by the Tx of hearts from pigs in which the gene for growth hormone receptors has been knocked out. Pigs in which 8 genetic manipulations have been carried out (all aimed at protecting the heart from the primate immune response) – which have not been available to any group previously - will form the basis of all our experiments but, in addition, growth hormone receptors will be deleted by a ninth genetic manipulation. If these two problems can be resolved, control of the innate immune response (by the genetic manipulations in the organ-source pig) and of the adaptive immune response (by a costimulation blockade-based immunosuppressive regimen introduced by us with proven success) will allow a comprehensive investigation of the hemodynamic function of the pig heart in supporting the baboon's circulation over a follow-up period of 6 months. We anticipate that the results of these studies will enable consideration to be given to initiating a clinical trial of cardiac xenotransplantation.