Project 2: Translating Cardiac Xenotransplantation

Massachusetts General Hospital, Boston MA

Investigators

Abstract

ABSTRACT To earn the confidence of the scientific community, regulatory authorities, and, ultimately, our patients that cardiac xenotransplantation deserves to be systematically evaluated in humans, it is essential to demonstrate consistent long-term, life-supporting heart xenograft survival in a preclinical model. This imperative is underscored by the occurrence of graft failure, apparently immunologically mediated, in Maryland’s two initial clinical heart xenotransplant cases. Preclinical data from the Maryland and Munich teams and our recent report demonstrate that, while the previously intractable barrier of delayed xenograft rejection (DXR) can sometimes be overcome, consistent long-term survival of genetically engineered (GE) heart xenografts in nonhuman primate (NHP) recipients has not yet been achieved. We propose to evaluate three likely explanations. First, emerging evidence suggests that knocking out the cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH) gene probably accounts for the shortened survival of triple-knockout (TKO) hearts in NHPs (but would be irrelevant in humans). Second, mechanistic studies from NHP and human recipients of pig hearts (and kidneys) strongly suggest an important role for NK cells in xenograft injury. Finally, immunosuppressive strategies for heart xenotransplantation need to be further refined in clinically relevant preclinical models to promote safe long- term recipient survival with minimal toxicity and infectious risks. To test these hypotheses, we propose to 1) evaluate the contribution of the CMAH gene KO to pathogenic immune injury occurring in 10-GE TKO heart xenografts, 2) downregulate host NK cell activity by expressing HLA-E in 9- or 10-GE hearts, and 3) evaluate the efficacy of αCD28 and dual αCD154/αCD28 costimulation pathway blockade in preventing/mitigating pathogenic immunity. These studies will be enhanced by Projects 1 and 3, which will test complementary but nonredundant hypotheses aimed at demonstrating consistent long-term life-supporting survival in NHP recipients and identify organ-specific differences, if they exist. State-of-the-art mechanistic assays and pathological studies coordinated by Core B will enable rapid cross-fertilization of insights gained in each project, the microbiological studies in Core C will provide critical data to ensure the safety of clinical xenotransplantation. Core D will provide the unique multi-GE pigs that are foundational to this Program. We anticipate that together, these highly interactive, innovative Projects supported by world-class Cores will generate one or more safe and effective protocols ready for clinical trial ‘translation’ by the end of the funding period. If successful, these studies would impact the entire field of transplantation.