- Dr. Simon C. Robson, Principal Investigator
- Dr. Imrana Qawi, Research Assistant
- Beth Israel Deaconess Medical Center, Boston, USA
- Disordered Thromboregulation in Xenotransplantation
Clinical transplantation is limited by the availability of suitable human organ donors. The proposed use of a unlimited supply of animal e.g. pig organs in clinical practice, termed xenotransplantation, could provide a bridge to a later successful human graft in a critically ill patient; or more optimistically, may even substitute for such a graft. Unfortunately, the clinical application of xenotransplantation, to date, has resulted in almost total failure.
Recent developments in the fields of xenotransplantation and blood vessel or vascular biology have greatly expanded our understanding of the mechanisms by which xenografts are rejected and have given new hope to the field. However, one additional novel barrier observed by the Applicant and colleagues is that of molecular incompatibility between the blood vessels of pig organs and primate/human blood coagulation factors and platelets. This causes rapid clotting within transplanted porcine xenografts in baboons with rapid loss. To mitigate against these effects, we propose to derive triple transgenic animals over-expressing two human natural anticoagulants (called tissue factor pathway inhibitor and thrombomodulin) and the thromboregulatory factor CD39, which was found by the Applicant to profoundly inhibit the activation of platelets irrespective of the species of origin. The project proposed in this application is a preliminary component of a long-term clinical xenotransplantation strategy, involving the genetic modification of donor pigs to render them biologically more compatible. We have first checked that the respective human cDNA’s can be functionally expressed in porcine vascular endothelium, either individually or in tandem. We now propose derivation of multi-transgenic mice, again checking that there are no deleterious effects and testing function of the over-expressed factors in relevant models of xenotransplantation.
This work will be judged successful if the data result in the testing of novel treatments to prolong xenograft survival and are of potential relevance for clinical transplantation.