# Translating Pathomechanisms into Treatment for Spinal Muscular Atrophies

> **NIH NIH R35** · JOHNS HOPKINS UNIVERSITY · 2022 · $1,002,012

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10401905
- **Project number:** 5R35NS122306-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Charlotte Jane Sumner
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,002,012
- **Award type:** 5
- **Project period:** 2021-05-05 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10401905

## Citation

> US National Institutes of Health, RePORTER application 10401905, Translating Pathomechanisms into Treatment for Spinal Muscular Atrophies (5R35NS122306-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10401905. Licensed CC0.

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