R35NS122306

Translating Pathomechanisms into Treatment for Spinal Muscular Atrophies - Project Summary

Spinal Muscular Atrophies (SMAs) are monogenetic motor neuron (MN) diseases that cause debilitating muscle weakness and often early mortality. My research program focuses on advancing therapeutics for two forms of SMA: proximal SMA caused by recessive, loss-of-function mutations of the Survival Motor Neuron 1 gene (SMN1) and distal SMA (DSMA) caused by dominant mutations of the Transient Receptor Potential Vanilloid 4 gene (TRPV4).

Our overarching approach is to integrate findings from human patients with experimentation in animal and iPSC-derived models to elucidate pathomechanistic pathways relevant to human disease and identify promising therapeutic opportunities. Here, we will leverage unique resources and state-of-the-art technologies to define factors limiting efficacy of current SMA therapeutics, characterize cellular and molecular mechanisms driving SMA pathology, and identify and validate novel therapeutic strategies.

Proximal SMA is at the forefront of rapidly evolving gene-targeting therapeutics, with two recently approved SMN-inducing treatments and a third under FDA review. While a transformative success, the clinical efficacy of these treatments is highly variable, ranging from normal attainment of early motor milestones to no improvement in motor function. In the last 5 years, our studies have revealed that proximal SMA pathology begins in utero, before treatments are currently initiated in patients. In both humans and mice, SMA MNs exhibit impaired maturation during gestation and precipitous neonatal degeneration, paralleled by a marked decline in SMN expression. Here, we will build on these observations to:

1) Dissect the specific mechanisms regulating SMN expression during development and treatment,
2) Identify the molecular mechanisms causing impaired maturation and degeneration of SMA MNs, and
3) Use these insights to develop novel and in utero SMA therapeutic strategies.

In parallel studies on DSMA, we have recently demonstrated that neuropathogenic mutations in TRPV4, a cell surface cation channel, disrupt regulatory protein-protein interactions and cause a gain of channel function. Existing TRPV4 antagonists have good tolerability in humans, making the channel a promising therapeutic target. Strikingly, mutant TRPV4 knock-in mouse models develop severe neurological phenotypes due to focal breakdown of blood-neural barriers (BNBs), which are rescued by selective genetic deletion of TRPV4 from endothelial cells (ECs) or treatment of symptomatic mice with TRPV4 antagonists. These studies suggest that TRPV4 activation can drive neuropathology in a non-cell autonomous manner by regulating BNBS. Here, we will:

1) Characterize protein interactions regulating TRPV4 channel activity,
2) Evaluate the role of TRPV4 in modulating EC barrier function, and
3) Assess TRPV4 antagonists as a therapeutic strategy in DSMA mice and ultimately other disorders characterized by BNB disruption.

Together, our studies will further our mechanistic understanding of SMA pathology, delineate novel therapeutic targets and strategies, and advance care of patients with SMAs and related neuromuscular diseases.

The Johns Hopkins 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]

Baltimore, Maryland 212051832 United States

Single Zip Code

Research Program Award (R35 Clinical Trial Optional) (RFA-NS-20-030)

Amendment Since initial award the total obligations have increased 400% from $1,058,846 to $5,290,574.