R37AI071068

ACUTE/CHRONIC LIMITATIONS TO TRANSCRIPTIONAL RNAI THERAPIES FOR INFECTIOUS AND OTHER LIVER DISEASES - DELIVERED RNAI PRODUCTS HAVE NOW BEEN FDA APPROVED FOR TREATING TWO GENETIC DISORDERS RESULTING FROM MUTATIONS AFFECTING GENES EXPRESSED IN THE LIVER. GENE VECTOR DELIVERED CASSETTES THAT PRODUCE SIRNAS HAVE AN ADVANTAGE FOR GENETIC DISORDERS BECAUSE OF THE POTENTIAL FOR A ONE-SHOT CURE. WE SOLVED ONE OF THE MYSTERIES OF HOW OVER EXPRESSION OF THERAPEUTIC RNAI (TRANSCRIPTIONAL RNAI) FROM AN AAV-U6 POLII PROMOTER DRIVEN SHRNA (AAV-SHRNA) CAUSED ACUTE LIVER TOXICITY AND CONTINUE TO STUDY THIS IN MORE DETAIL. WHEN SIRNAS FROM SUCH A SOURCE REACHED 12% OR MORE OF THE TOTAL MIRNA READS THERE WAS A 10% REDUCTION IN THE FIRST SYNTHESIZED MIR122 ISOFORM (BUT NOT THE OTHER MIRNAS) AND THIS INDUCED ACUTE LIVER TOXICITY EXEMPLIFIED BY ELEVATED LIVER ENZYMES AND IN SOME CASES LIVER FAILURE AND DEATH. BECAUSE GERMLINE KNOCKOUT OF MIR122 HAS A MUCH LESSER PHENOTYPE, WE HYPOTHESIZE THE DISCORDANCE IN THESE OUTCOMES IS RELATED TO THE DIFFERENTIAL EXPRESSION OF THE MIR122 PRECURSOR RNA TRANSCRIPT KNOWN AS LONG-NON-CODING RNA 122 (LNC122) AND THAT THESE TWO RNAS HAVE SEPARATE BUT COORDINATED FUNCTIONS. WE PROPOSE TO ELUCIDATE THE MOLECULAR FUNCTION OF NUCLEAR LOCALIZED LNC122 RNA AND BY REMOVING LNC122 AND MIR122 RNAS AND THEN REINTRODUCING THE DIFFERENT INDIVIDUAL RNA COMPONENTS IN CELLS, MOUSE LIVER AND HEPATOCELLULAR CARCINOMA MODELS. THIS WILL ALLOW US TO SEPARATE THE INDIVIDUAL FUNCTIONS OF THE RNA PRODUCTS. WE WILL ALSO MAP THE LNC122 CHROMATIN INTERACTIONS. THESE STUDIES ARE IMPORTANT BECAUSE NOT ONLY DOES THE MIR122/LNC122 GENE HAVE A TUMOR SUPPRESSOR FUNCTION, BUT IT IS ALSO KNOWN TO HAVE EFFECTS ON NORMAL LIVER REGENERATION, FORMATION OF HEPATOCELLULAR CARCINOMA, AND LIVER FIBROSIS ASSOCIATED WITH VARIOUS LIVER DISEASES SUCH AS NASH, LIPID METABOLISM, AND VIRAL HEPATITIS INFECTION. NEWER STRATEGIES TO TARGET GENE TRANSFER/EXPRESSION OUTSIDE THE LIVER CONTAIN TRANSGENES WITH MIR122 TARGETS IN THE 3'UTR TO EXCLUDE LEAKY EXPRESSION IN HEPATOCYTES. THIS LIKE SOME OF THE ANTISENSE MIR122 PRODUCTS TESTED IN CLINICAL TRIALS, AND HEPATITIS VIRUS B AND INFECTIONS RESULT IN THE SPONGING OF MIR122 AND THE LONG-TERM EFFECTS OF THIS ARE UNCLEAR. AT THE END OF THE GRANTING PERIOD, WE WILL HAVE A BETTER UNDERSTANDING OF THE FUNCTION OF THE VARIOUS RNA PRODUCTS PRODUCED FROM THE LNC122-MIR122 LOCUS AND THEIR ROLE IN CELLULAR HOMEOSTASIS AND HOW THIS MAY EFFECTIVELY LIMIT RNAI BASED THERAPEUTICS. MOREOVER, AS WE LEARN MORE ABOUT THE FUNCTION OF THIS GENETIC LOCUS IT WILL PROVIDE MORE INSIGHTS INTO HOW IT PARTICIPATES IN THE DISEASE PROCESSES NOTED. THIS MAY PROVIDE NEW INSIGHTS INTO MORE OPTIMAL MEANS TO TREAT PATIENTS WITH A VARIETY OF GENETIC AND ACQUIRED DISEASES.

The Leland Stanford Junior 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]

Stanford, California 94305 United States

Single Zip Code

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

Amendment Since initial award the total obligations have increased 489% from $597,074 to $3,515,317.