R01AI194953

IMMUNOMODULATION IN AAV GENE THERAPY - ABSTRACT RECOMBINANT AAV VECTORS HAVE EMERGED AS PROMISING GENE DELIVERY VEHICLES IN THE TREATMENT OF MONOGENIC DISORDERS. WITH 6 DIFFERENT FDA APPROVED AAV-BASED THERAPIES, MANY ADDITIONAL DISEASE TARGETS REQUIRING SYSTEMIC DOSING CONTINUE ADVANCING TOWARDS THE CLINIC. HOWEVER, IMMUNE RESPONSES ARISING FROM PRIOR NATURAL AAV EXPOSURE OR NASCENT EXPOSURE TO RECOMBINANT AAV VECTORS DOSED IN HUMAN SUBJECTS POSES A MAJOR CHALLENGE. EVIDENCE FROM MULTIPLE GENE THERAPY CLINICAL TRIALS CONFIRMS THAT HIGH VECTOR DOSES CAN TRIGGER CYTOKINE RELEASE LEADING TO NAUSEA, FEVER, AND VOMITING, AND MANIFEST IN LIVER TOXICITY (ELEVATED ENZYMES). IN SOME PATIENTS, COMPLEMENT ACTIVATION FOLLOWING SYSTEMIC AAV DOSING HAS BEEN SHOWN TO RESULT IN THROMBOTIC MICROANGIOPATHY (TMA) AND ACUTE KIDNEY INJURY (ATYPICAL HEMOLYTIC UREMIC SYNDROME-LIKE), THROMBOCYTOPENIA, MYOCARDIAL INJURY, AND EVEN DEATH. MANY OF THESE ADVERSE REACTIONS CAN BE ATTRIBUTED TO AAV CAPSID-ANTIBODY INTERACTIONS HIGHLIGHTING A MAJOR (IF NOT PREDOMINANT) ROLE FOR HUMORAL IMMUNITY. PROPHYLACTIC MEASURES OR SYMPTOM MANAGEMENT HAVE GENERALLY INCLUDED PLASMAPHERESIS, ADMINISTRATION OF TAPERING, HIGH DOSES OF GLUCOCORTICOSTEROIDS, HEMODIALYSIS, PLATELET TRANSFUSION, DIFFERENT DRUGS OR MONOCLONAL ANTIBODIES TO BLOCK COMPLEMENT/B CELL ACTIVATION OR INDUCE B CELL DEPLETION AMONGST OTHERS. MORE RECENTLY, PRECLINICAL TESTING OF AGENTS SUCH AS IMLIFIDASE OR VYVGART FOR PROMOTING IGG CLEARANCE HAS BEEN INITIATED. HOWEVER, THESE CURRENT MANAGEMENT OR MITIGATION STRATEGIES FOR THESE CLINICAL SEQUALAE ARE APPLIED ON A CASE-BY-CASE BASIS WITH NO SPECIFIC CONSENSUS IMMUNOMODULATORY REGIMENS (IMRS) IN PLACE. THUS, THERE IS A CLEAR AND URGENT NEED TO BETTER UNDERSTAND, PRECLINICALLY MODEL AND MANAGE THESE COMPLEX SEQUALAE (FOCUS OF THE CURRENT PROPOSAL). TO THIS END, OUR LAB RECENTLY ENGINEERED A NOVEL IMMUNOMODULATORY AGENT, ICEMG – A RECOMBINANT, DUAL ACTIVITY PROTEASE THAT CAN SELECTIVELY AND EFFICIENTLY CLEAVE HUMAN AND MONKEY IGG/IGM. HERE, WE PROPOSE TO BUILD ON OUR EXCITING FINDINGS AND VALIDATE THAT ICEMG IS A POTENT BLOCKER OF COMPLEMENT ACTIVATION AS WELL AS MODULATOR OF B CELL SIGNALING PATHWAYS IN HUMAN MODELS IN VITRO AND HUMANIZED MICE AS WELL AS NON-HUMAN PRIMATES IN VIVO, THEREBY CHARTING A PATH FOR FIRST-IN-HUMAN PHASE I TRIALS UTILIZING THIS IMR. FURTHER, WE WILL ENGINEER AND CHARACTERIZE NEXT GENERATION IMMUNOMODULATORS (ICERX) FOR CLINICAL TRANSLATION. IF SUCCESSFUL, THE CURRENT PROPOSAL WILL ENABLE DEVELOPMENT OF NEW AND IMPROVED IMR, ESSENTIAL FOR THE SUCCESS OF AAV GENE TRANSFER VECTORS IN THE CLINIC. THE PROPOSED STRATEGIES MAY ALSO PAVE THE PATH FOR CLINICAL APPLICATIONS IN AUTOIMMUNE DISEASE AND ORGAN TRANSPLANTATION.

Duke University

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]

North Carolina United States

State-Wide

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)