R01AI201152

HEMATOPOIETIC STEM/PROGENITOR CELL BASED CAR THERAPY TARGETING HIV - PROJECT SUMMARY/ABSTRACT HIV DISEASE REMAINS A CONSIDERABLE PUBLIC HEALTH CONCERN WITHOUT A PRACTICABLE CURE. DRUG-BASED THERAPY CAN CONTROL HIV BUT IS COSTLY, HAS SEVERE SIDE EFFECTS, AND IS NOT CURATIVE. STEM-CELL BASED THERAPIES HAVE PROVIDED THE ONLY KNOWN CURES FOR HIV INFECTION, WITH ONLY A HANDFUL OF INDIVIDUALS FUNCTIONALLY CURED TO DATE. HOWEVER, REPLICATING THESE SUCCESSES HAS BEEN CHALLENGING DUE TO THE HIGH TOXICITIES OF TREATMENT, NEED FOR TRANSPLANT ANTIGEN MATCHING, AND REQUIRE EXTENSIVE MYELOABLATION. HOWEVER, THESE “CURES” STRONGLY SUGGEST THAT IMMUNE SYSTEM MODIFICATION INVOLVING HEMATOPOIETIC STEM/PROGENITOR CELL (HSPC) TRANSPLANTATION CAN PLAY A STRONG ROLE ALLOWING HIV CLEARANCE FROM THE BODY. WE AIM TO ACHIEVE A HIV-1 CURE BY ENHANCING AND OPTIMIZING ANTI-HIV CELLULAR IMMUNE RESPONSES THROUGH GENETIC MODIFICATION OF AUTOLOGOUS HEMATOPOIETIC STEM/PROGENITOR CELLS (HSPCS) WITH AN ANTI-HIV CHIMERIC ANTIGEN RECEPTOR (CAR) MOLECULE (CAR-HSPC). UNLIKE COMBINED ANTIRETROVIRAL TREATMENT (ART), WHICH CANNOT ERADICATE HIV DUE TO PERSISTENT RESERVOIRS, OUR APPROACH TARGETS LIFELONG ANTI-HIV RESPONSES FOR HIV CLEARANCE. WE WILL IMPROVE THE ENGRAFTMENT OF CAR-MODIFIED STEM CELLS BY USING CLINICALLY RELEVANT CONDITIONING METHODS, MAINTAIN LONG-TERM PROGENITOR PHENOTYPE IN CAR STEM CELLS FOR REPOPULATION CAPABILITY, AND IMPROVE HOMING TO THE BONE MARROW. ADDITIONALLY, WE WILL CHARACTERIZE THE DIFFERENTIATION AND THERAPEUTIC EFFECTS OF HSPC-DERIVED CAR MODIFIED IMMUNE CELLS IN VARIOUS TISSUE RESERVOIRS USING HUMANIZED MOUSE MODELS. WE WILL DEVELOP AN IN VIVO TARGETING REGIMEN INCORPORATING STEM CELL TARGETED NANOCAPSULES ENCAPSULATING CAR LENTIVIRUS TO GENERATE CAR-MODIFIED STEM CELLS IN VIVO AND EVALUATE FOR FEASIBILITY AND EFFICACY. OUR PROPOSED STUDY WILL PROVIDE CRUCIAL INSIGHTS FOR INVESTIGATIONAL NEW DRUG (IND) DEVELOPMENT OF HSPC-BASED CAR IMMUNOTHERAPIES, POTENTIALLY LEADING TO ART-FREE HIV SUPPRESSION AND A FUNCTIONAL CURE.

Los Angeles University Of California

<P>THE GOALS ARE:</P><UL><LI>TO FOSTER FUNDAMENTAL CREATIVE DISCOVERIES, INNOVATIVE RESEARCH STRATEGIES, AND THEIR APPLICATIONS AS A BASIS FOR ULTIMATELY PROTECTING AND IMPROVING HEALTH;</LI><LI>TO DEVELOP, MAINTAIN, AND RENEW SCIENTIFIC HUMAN AND PHYSICAL RESOURCES THAT WILL ENSURE THE NATION'S CAPABILITY TO PREVENT DISEASE;</LI><LI>TO EXPAND THE KNOWLEDGE BASE IN MEDICAL AND ASSOCIATED SCIENCES IN ORDER TO ENHANCE THE NATION'S ECONOMIC WELL-BEING AND ENSURE A CONTINUED HIGH RETURN ON THE PUBLIC INVESTMENT IN RESEARCH; AND</LI><LI>TO EXEMPLIFY AND PROMOTE THE HIGHEST LEVEL OF SCIENTIFIC INTEGRITY, PUBLIC ACCOUNTABILITY, AND SOCIAL RESPONSIBILITY IN THE CONDUCT OF SCIENCE.</LI></UL><P>IN REALIZING THESE GOALS, THE NIH PROVIDES LEADERSHIP AND DIRECTION TO PROGRAMS DESIGNED TO IMPROVE THE HEALTH OF THE NATION BY CONDUCTING AND SUPPORTING RESEARCH:</P><UL><LI>IN THE CAUSES, DIAGNOSIS, PREVENTION, AND CURE OF HUMAN DISEASES;</LI><LI>IN THE PROCESSES OF HUMAN GROWTH AND DEVELOPMENT;</LI><LI>IN THE BIOLOGICAL EFFECTS OF ENVIRONMENTAL CONTAMINANTS;</LI><LI>IN THE UNDERSTANDING OF MENTAL, ADDICTIVE AND PHYSICAL DISORDERS; AND</LI><LI>IN DIRECTING PROGRAMS FOR THE COLLECTION, DISSEMINATION, AND EXCHANGE OF INFORMATION IN MEDICINE AND HEALTH, INCLUDING THE DEVELOPMENT AND SUPPORT OF MEDICAL LIBRARIES AND THE TRAINING OF MEDICAL LIBRARIANS AND OTHER HEALTH INFORMATION SPECIALISTS.</LI></UL>

93.855 - Allergy and Infectious Diseases Research

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

Los Angeles, California 90095 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-25-301)