U01AI153612

CRISPR-Modified Cardiac Xenograft Transplantation - Summary Abstract:

The past three years have witnessed two major breakthroughs in heart xenotransplantation. First, the previously intractable barrier of delayed xenograft rejection (DXR) has been overcome in the pig-to-baboon heart xenomodel. In this model, DXR is manifest primarily as consumptive coagulopathy (CC) in the recipient and thrombotic microangiopathy (TM) in the graft.

Working in the heterotopic model in baboons, our "Mohiuddin/NIH" group used genetically modified GTKO.HCPRP.HTBM hearts and a treatment regimen including "induction" T and B depletion, MMF, and steroids - all clinically used drugs - with an experimental monoclonal antibody directed against CD40. DXR was prevented for as long as CD40 treatment was continued, and in one instance xenograft survival was extended beyond two years.

The second major advance came from the Munich group, who reported consistent survival of orthotopic pig heart xenograft recipients beyond 180 days using our immunomodulatory regimen and GTKO.HCPRP.HTBM hearts. Accomplishing consistent survival of orthotopic heart xenografts had previously been prevented by initial xenograft dysfunction (IXD), a phenomenon refractory to concerted efforts by multiple experienced clinical transplant teams. Importantly, the Munich group found that minimizing graft ischemia was necessary and sufficient to consistently prevent IXD. Discovering that ischemia minimization was sufficient to overcome the IXD barrier is a "breakthrough" advance, even as the mechanism of improved graft protection by ischemia minimization is not yet well understood.

In this project, we hypothesize that IXD mechanisms that injure GTKO.HCPRP.HTBM hearts may be addressed by the additional xeno-focused genetic modifications expressed in one or more versions of Pig 2.0, created by our collaborators at eGenesis using innovative CRISPR-driven gene editing tools. Pig 2.0 is designed to address multiple known xeno-specific injury mechanisms through a combination of 12 xeno-targeted genetic modifications.

This project takes advantage of the availability of several well-defined versions of Pig 2.0, our deep experience with multiple in vitro, ex vivo, and in vivo heart xeno models, and a robust mechanistic assay capability to determine whether Pig 2.0 is protected from heart IXD, with or without ischemia minimization (Aim 1). Specifically, we will use these unique resources to learn a) whether versions of Pig 2.0 containing a coagulation cascade regulatory gene cassette are protected from IXD; b) whether ischemia minimization is necessary and/or sufficient to prevent IXD in susceptible Pig 2.0 hearts; and c) to define a clinically acceptable immunosuppression regimen for Pig 2.0 hearts in baboons that is consistently safe and effective (Aim 2).

Results from this project will yield insights likely to catalyze progress for other cell and organ xenografts, and inform clinical heart xenotransplantation trial design.

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]

Massachusetts United States

State-Wide

Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-19-056)

Amendment Since initial award the total obligations have increased 300% from $795,705 to $3,182,820.