U01NS145218

PRECISION EDITING OF GRANULIN MUTATIONS THAT CAUSE FRONTOTEMPORAL DEMENTIA - PROJECT SUMMARY FRONTOTEMPORAL DEMENTIA (FTD) IS THE MOST COMMON FORM OF PRESENILE DEMENTIA BEFORE THE AGE OF 60, AND NO EFFECTIVE TREATMENTS ARE AVAILABLE. 40% OF FTD CASES ARE FAMILIAL AND ONE OF THE MOST COMMON GENES WITH FTD-CAUSING MUTATIONS IS GRANULIN (GRN), WHICH ENCODES PROGRANULIN (PGRN), A SECRETED REGULATORY PROTEIN. GRN MUTATIONS, SUCH AS THE MOST PREVALENT NONSENSE MUTATION C.1477C>T (P.R493X), RESULT IN PGRN HAPLOINSUFFICIENCY, AND ATTEMPTS AT DEVELOPING SMALL MOLECULE, BIOLOGIC, AND GENE REPLACEMENT THERAPIES HAVE PROVEN CHALLENGING DUE TO INHERENT TOXICITIES THAT RESULT FROM PGRN OVEREXPRESSION. PRECISION GENOME EDITING STRATEGIES TO CORRECT THE ENDOGENOUS GENE AND RESTORE NATIVELY REGULATED PROGRANULIN PRODUCTION, EVEN AT <100% EDITING EFFICIENCY, THEREFORE REPRESENT A SUPERIOR THERAPEUTIC PATH. THE TWO BEST-DEVELOPED MODES OF PRECISION EDITING IN VIVO ARE BASE EDITING (BE) AND PRIME EDITING (PE), EACH WITH COMPLEMENTARY SETS OF ADVANTAGES AND DISADVANTAGES FOR ADDRESSING PATHOGENIC C:G-TO-T:A MUTATIONS SUCH AS GRN C. 1477C>T (P.R493X). IN THIS PROPOSAL, WE HAVE ASSEMBLED AN EXPERIENCED, MULTIDISCIPLINARY TEAM TO DEVELOP A MAXIMALLY EFFECTIVE THERAPEUTIC EDITING APPROACH TO TREAT GRN-FTD CAUSED BY THIS MUTATION. WE WILL ASSESS CANDIDATE APPROACHES THAT EMPLOY EITHER BE OR PE, INITIALLY IN GRN-FTD PATIENT INDUCED PLURIPOTENT STEM CELL (IPSC)-DERIVED NEURONS AND GLIAL CELLS TO CORRECT GRNR493X, AND THEN COMPARE THEIR EFFECTIVENESS TO PREVENT DISEASE PROGRESSION IN A HUMANIZED GRNR493X MOUSE THAT FAITHFULLY MODELS SOME ASPECTS OF FTD. OUR PE DEVELOPMENT WILL ALSO TEST THE FEASIBILITY OF REWRITING LARGER EXON SEGMENTS, THEREBY ENABLING CORRECTION OF ADDITIONAL MUTATIONS FROM THE PATIENT POPULATION TO BE ADDRESSED WITH A SINGLE CORRECTIVE REAGENT. SAFE AND EFFECTIVE DELIVERY REPRESENTS ONE IMPORTANT CHALLENGE IN THERAPEUTIC GENOME EDITING, ESPECIALLY IN THE CENTRAL NERVOUS SYSTEM. WE WILL ADDRESS THIS CHALLENGE BY ADVANCING BOTH VIRAL VECTOR DELIVERY AND NOVEL NON-VIRAL DELIVERY STRATEGIES THAT WE ARE DEVELOPING TO DEFINE THE SAFEST AND MOST EFFECTIVE DELIVERY MODALITY FOR THESE EDITING TECHNOLOGIES. THIS WORK PROMISES TO LEAD TO A SPECIFIC, EFFECTIVE THERAPEUTIC INTERVENTION FOR A DEVASTATING AND CURRENTLY UNTREATABLE FORM OF HERITABLE DEMENTIA. OUR STUDIES WILL ALSO ADVANCE PLATFORM TECHNOLOGIES AND ESTABLISH A BLUEPRINT FOR DEVELOPING CLINICAL GENOME EDITING APPROACHES, LEVERAGING THESE TOOLS FOR ADDITIONAL MUTATIONS THAT CAUSE FTD AND OTHER FORMS OF DEMENTIA.

University Of Massachusetts Medical School

(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM, TO INCREASE 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. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM, TO STIMULATE AND FOSTER 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.

93.866 - Aging Research

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

National Institute on Aging (NIA) [HHS - NIH]

Worcester, Massachusetts 01655 United States

Single Zip Code

Optimization of Genome Editing Therapeutics for Alzheimer's Disease-Related Dementias (ADRD) (U01 - Clinical Trials Not Allowed) (RFA-NS-24-037)