U19AI191384

PRECLINICAL TRANSLATION OF KIDNEY, HEART, AND LUNG XENOTRANSPLANTATION - ABSTRACT TO EARN THE CONFIDENCE OF THE SCIENTIFIC COMMUNITY, REGULATORY AUTHORITIES, AND, ULTIMATELY, OUR PATIENTS THAT XENOTRANSPLANTATION DESERVES TO BE SYSTEMATICALLY EVALUATED IN HUMANS, IT IS ESSENTIAL TO DEMONSTRATE CONSISTENT LONG-TERM, LIFE-SUPPORTING XENOGRAFT SURVIVAL IN A PRECLINICAL MODEL. ALTHOUGH WE HAVE ACCOMPLISHED OVER ONE YEAR OF LIFE-SUPPORTING SURVIVAL IN NONHUMAN PRIMATES (NHPS) USING KIDNEY XENOGRAFTS WITH KNOCKOUT (KO) OF GENES ENCODING THREE MAJOR CARBOHYDRATE XENOANTIGENS (GALT, B4GALNT2 AND CMAH KO, TRIPLE KNOCK-OUT, TKO) AND MULTIPLE ADDITIONAL HUMAN TRANSGENES, THROMBOTIC MICROANGIOPATHY (TMA) AND ANTIBODY-MEDIATED REJECTION (AMR) REMAIN THE PRIMARY, PREVALENT CAUSES OF THE TKO-BASED MULTI-GENE EDITED (MULTI-GE) KIDNEY AND ALSO HEART AND LUNG XENOGRAFT LOSS. WE WILL TEST FOUR WORKING HYPOTHESES REGARDING THE REASON FOR THESE PRECLINICAL AND, IN THE CASE OF HEART XENOGRAFTS, CLINICAL FAILURES. FIRST, STRONG EVIDENCE IMPLICATES THAT KNOCKING OUT THE CMAH GENE IN TKO (BUT NOT DKO) SWINE UNVEILS THE EXPRESSION OF A ‘4TH ANTIGEN’ THAT IS THE TARGET OF INNATE IMMUNITY IN NHP BUT IS IRRELEVANT IN HUMAN RECIPIENTS. WE WILL EVALUATE THE CONTRIBUTION OF THE CMAH GENE KO TO PATHOGENIC IMMUNE INJURY OCCURRING IN TKO ORGAN XENOGRAFTS BY COMPARING THE PERFORMANCE, HISTOLOGY, AND MOLECULAR PROFILE OF KIDNEYS, HEARTS, AND LUNGS FROM 10-GE TKO TO THOSE FROM 9-GE DKO PIG. WE EXPECT RESULTS USING DKO-BASED 9-GE PIG ORGANS WILL ENABLE THE DESIGN OF IND-QUALIFYING ORGAN XENOGRAFT TRIALS FOR ONE OR MORE ORGANS. SECOND, BASED ON COMPELLING IN VITRO, EX VIVO, AND IN VIVO EVIDENCE THAT NK CELLS CONTRIBUTE SIGNIFICANTLY TO HEART, KIDNEY, AND LUNG XENOGRAFT INJURY, WE WILL TEST THE HYPOTHESIS THAT ACTIVATION OF NK CELLS WILL BE INHIBITED BY HLA-E EXPRESSION ON PIG ENDOTHELIUM, WHICH WILL ATTENUATE INFLAMMATION AND INJURY BOTH IN THE XENOGRAFT AND SYSTEMICALLY IN THE RECIPIENT. THIRD, WE WILL OPTIMIZE THE IMMUNOSUPPRESSIVE REGIMEN FOR KIDNEY, HEART, AND LUNG XENOGRAFTS. FINALLY, WE WILL EVALUATE COMPLEMENT INHIBITION, CD11B BLOCKADE, DONOR MACROPHAGE DEPLETION, AND ISCHEMIA MINIMIZATION AS STRATEGIES TAILORED TO EACH ORGAN WITH THE GENERAL OBJECTIVE OF EFFECTIVELY MODULATING INFLAMMATION IN THE GRAFT AND ORGAN XENOGRAFT RECIPIENT. THE HYPOTHESES, AIMS, AND EXPERIMENTAL APPROACHES ARE HARMONIZED BETWEEN EACH PROJECT AND SUPPORTED BY ADMINISTRATIVE, PATHOLOGY MECHANISTIC, INFECTIOUS DISEASE, AND SWINE PRODUCTION CORES, WHICH TOGETHER WILL FACILITATE A COORDINATED EFFORT TO UNDERSTAND AND OVERCOME THE REMAINING BARRIERS TO THE CLINICAL APPLICATION OF KIDNEY HEART, AND LUNG XENOGRAFTS. TO OUR KNOWLEDGE, MGH IS THE ONLY CENTER IN THE WORLD CAPABLE OF PERFORMING COMPREHENSIVE COMPARATIVE STUDIES OF KIDNEY, HEART, AND LUNG XENOTRANSPLANTATION IN PRECLINICAL MODELS. WE ANTICIPATE THAT TOGETHER, THESE HIGHLY INTERACTIVE PROJECTS WILL GENERATE ONE OR MORE SAFE AND EFFECTIVE PROTOCOLS READY FOR CLINICAL TRIAL BY THE END OF THE FUNDING PERIOD. IF SUCCESSFUL, THESE STUDIES WOULD IMPACT THE ENTIRE FIELD OF TRANSPLANTATION.

The General Hospital Corporation

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Charlestown, Massachusetts 02129 United States

Single Zip Code

Immunobiology of Xenotransplantation (U19 Clinical Trial Not Allowed) (RFA-AI-24-020)