RF1NS105479

PRE-SYMPTOMATIC FAMILIAL ALS (PRE-FALS) STUDY: FROM PRODROME AND BIOMARKERS TO ALS/FTD PREVENTION - PROJECT SUMMARY AMYOTROPHIC LATERAL SCLEROSIS (ALS) REMAINS A FATAL NEURODEGENERATIVE DISORDER, IN PART BECAUSE DIAGNOSIS IS DELAYED AND TREATMENT IS INITIATED LATE IN DISEASE COURSE. THERAPEUTIC SUCCESS IS MOST LIKELY WHEN TREATMENT IS INITIATED EARLY, IDEALLY WHILE STILL PRE-SYMPTOMATIC. UNAFFECTED CARRIERS OF PATHOGENIC VARIANTS ASSOCIATED WITH EITHER ALS OR BOTH ALS AND FRONTOTEMPORAL DEMENTIA (FTD), HEREAFTER COLLECTIVELY REFERRED TO AS ALS/FTD ARE THE ONLY POPULATION CURRENTLY KNOWN TO BE AT SIGNIFICANTLY ELEVATED RISK FOR THESE DISORDERS, AND IN WHOM THE STUDY OF PRE-SYMPTOMATIC DISEASE IS FEASIBLE. PRE-SYMPTOMATIC FAMILIAL ALS (PRE-FALS) IS THE FIRST AND MOST LONGSTANDING NATURAL HISTORY AND BIOMARKER STUDY OF THIS POPULATION. THE OVERARCHING GOALS OF PRE-FALS ARE TO: (A) UNDERSTAND PRE-SYMPTOMATIC ALS/FTD; (B) DISCOVER THE EARLIEST MARKERS OF DISEASE; AND (C) EMPOWER ALS/FTD PREVENTION. THROUGH PRE-FALS WE HAVE DEVELOPED A CONCEPTUAL FRAMEWORK AND PROPOSED A LEXICON FOR DESCRIBING THE PRE-SYMPTOMATIC STAGES OF THESE DISEASES; IDENTIFIED NEUROFILAMENT LIGHT CHAIN AS THE FIRST RISK/SUSCEPTIBILITY BIOMARKER THAT PREDICTS PHENOCONVERSION TO CLINICALLY MANIFEST ALS; DISCOVERED AND DEVELOPED DIAGNOSTIC CRITERIA FOR MILD MOTOR IMPAIRMENT (MMI), A NOVEL CLINICAL SYNDROME AND PRODROMAL CLINICAL MARKER OF DISEASE; AND DESIGNED AND LAUNCHED, IN COLLABORATION WITH AN INDUSTRY PARTNER, THE FIRST-EVER ALS PREVENTION TRIAL (ATLAS) IN A SUBSET OF THE SOD1 POPULATION. PRE-FALS IS ALSO A UNIQUE RESOURCE FOR PRE- SYMPTOMATIC CLINICAL MARKER AND BIOMARKER DISCOVERY, GIVEN THE LONGITUDINALLY COLLECTED DEEP PHENOTYPIC DATA (MOTOR AND COGNITIVE/BEHAVIORAL) AS WELL AS BIOLOGICAL SPECIMENS, BOTH BEFORE AND AFTER PHENOCONVERSION. IN THIS RENEWAL APPLICATION, WE WILL EXPAND UPON OUR PIONEERING WORK THAT LED TO ATLAS, TO PREPARE FOR PREVENTION TRIALS IN OTHER (AND LARGER) POPULATIONS AT GENETIC RISK FOR ALS/FTD, WHICH WE BELIEVE WILL REQUIRE A MULTIMODAL APPROACH. SPECIFICALLY, WE WILL: CHARACTERIZE THE PRODROMAL STAGES OF ALS AND FTD AMONG ALS/FTD- ASSOCIATED PATHOGENIC VARIANT CARRIERS (AIM 1); CHARACTERIZE THE LONGITUDINAL TRAJECTORY (AND VARIABILITY) OF AN ARRAY OF CLINICAL MARKERS AND BIOMARKERS IN THE PRE-SYMPTOMATIC PHASE OF DISEASE, WHICH COMPRISES BOTH CLINICALLY SILENT AND PRODROMAL STAGES (AIM 2); AND IDENTIFY THE SUBGROUP OF INDIVIDUALS, BASED ON THEIR CLINICAL AND BIOMARKER PROFILE, WHO ARE AT GREATEST RISK FOR PROGRESSING TO CLINICALLY MANIFEST DISEASE (ALS OR FTD) WITHIN 5 YEARS (AIM 3). IN TURN, THE RESULTS OF THE WORK OUTLINED IN THIS PROPOSAL WILL FUEL TRANSLATION OF PRODROMAL DISEASE AND BIOMARKER DISCOVERY INTO VIABLE STRATEGIES FOR PREVENTING BOTH ALS AND FTD.

University Of Miami

(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]

Florida United States

State-Wide

Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional) (PAR-22-093)