U01NS124974

Trial Readiness and Endpoint Assessment in LGMDR1 (Treating-LGMDR1)

The overall goal of this project is to develop reliable and valid Clinical Outcome Assessments (COAs) and biomarkers for Limb Girdle Muscular Dystrophy R1 (LGMDR1) to hasten therapeutic development.

LGMDR1 is an autosomal recessive form of LGMD due to a loss of function in muscle structural gene CAPN3. This loss of function leads to progressive weakness of the shoulder and hip girdle muscles and therefore progressive disability, including loss of ambulation or the ability to maintain a job. There are no FDA approved treatments for LGMDR1, which represents a large unmet medical need.

LGMDR1 is amenable to gene replacement therapies; and in recent years, a systemic gene therapy has been approved for Spinal Muscular Atrophy and is in development for LGMDR4. At least five companies have gene-targeted therapies or regenerative medicine approaches in development for LGMDR1, creating a situation where therapeutic development has outstripped our ability to prepare for clinical trials.

The rationale for this study is that the Northstar Ambulatory Assessment for LGMD (NSAD), modified from a widely accepted functional assessment in a related disorder, requires validation as a primary endpoint in LGMDR1. Given the slowly progressive nature of the condition, we also anticipate that a biomarker, such as muscle fat fraction, is required for early phase therapeutic trials to provide an early signal of effect.

We propose the following specific aims:
1) To validate the NSAD as a primary endpoint for LGMDR1; and
2) To validate quantitative muscle MRI as a monitoring biomarker in LGMDR1.

To achieve our aims, we plan to leverage an existing LGMD clinical research network to conduct a 24-month longitudinal observational study of 100 clinically affected, ambulatory and genetically defined LGMDR1 individuals at 12 sites on our LGMD research network. We hypothesize that the NSAD will be amenable to multi-site training, reliable, related to patient-identified areas of disease impact, and useful for power and sample size planning for forthcoming clinical trials. The muscle fat fraction is likely to demonstrate progression in advance of change on the NSAD. Combined, we will model disease progression to define the range of scores on the NSAD that would define the optimal therapeutic trial population.

At the completion of this study, we will have validated the NSAD as a primary endpoint for LGMDR1; validated muscle fat fraction as an ideal biomarker for LGMDR1; established the clinical trial characteristics, including inclusion/exclusion criteria, sample size, and clinically important difference for therapeutic trials. Given the significant progress in therapeutic development for LGMDR1, the development of appropriate COAs and biomarkers for this population is an urgent need.

Virginia Commonwealth University

(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.

93.853 - Extramural Research Programs in the Neurosciences and Neurological Disorders

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

Richmond, Virginia 232191539 United States

Single Zip Code

Clinical Trial Readiness for Rare Neurological and Neuromuscular Diseases (U01 Clinical Trial Not Allowed) (PAR-19-220)

Amendment Since initial award the total obligations have increased 165% from $1,139,041 to $3,017,334.