# Impaired axon development in SMA

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $417,505

## Abstract

PROJECT SUMMARY
The motor neuron disease spinal muscular atrophy (SMA) is the leading inherited cause of death in infancy
and childhood. It is caused by recessive mutations of the survival motor neuron 1 gene (SMN1). All patients
retain one or more copies of the homologous SMN2 gene, but it produces inadequate levels of SMN protein
due to an alternative splice event. Novel therapeutics aiming to modulate SMN2 splicing including antisense
oligonucleotides and small molecules are recently FDA-approved or currently in clinical trials in SMA patients.
While this is a success, it remains unknown why many patients have inadequate therapeutic responses.
Defining the optimal timing and tissue targeting of SMN induction has been limited by poor understanding of
early disease pathology in patients. To address this knowledge gap, in preliminary studies we examined
ventral root axons in severe SMA patients and model mice and discovered marked impairments of motor axon
sorting and radial growth, which begin prenatally and are followed by degeneration of immature axons
perinatally. This project aims to determine if these pathologies may underlie the early disease onset,
stereotypical pattern of weakness, and precipitous decline of severe SMA patients. In Specific Aim 1, we will
characterize the temporal and topographic patterns of this pathology in both a severe and milder SMA mouse
model and in human samples. In Specific Aim 2, we will define the cellular contributors to this pathology
utilizing a series of conditional SMA mouse lines expressing increased SMN specifically in either motor
neurons, Schwann cells, or muscle. We will also evaluate whether neuregulin 1 type III (NRG1-III), a key
regulator of peripheral axon development, is dysregulated in SMA and explore whether overexpression of
NRG1-III can ameliorate SMA axonal pathologies. Finally, in Specific Aim 3, we will establish when SMN-
inducing drugs, including SMN2 splice-switching antisense oligonucleotides and the small molecule SMN-C3,
must be delivered to restore axonal maturation, prevent motor unit degeneration, and provide optimal
phenotypic rescue. Together, these studies will characterize a newly recognized and prominent pathology of
severe SMA patients and define the optimal timing of therapeutics. The results of these investigations will
provide important insights regarding the outcomes of patients currently enrolled in clinical trials, influence the
design of future trials, and potentially uncover novel SMA therapeutic targets.

## Key facts

- **NIH application ID:** 9899329
- **Project number:** 5R01NS106875-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Charlotte Jane Sumner
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $417,505
- **Award type:** 5
- **Project period:** 2018-04-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899329

## Citation

> US National Institutes of Health, RePORTER application 9899329, Impaired axon development in SMA (5R01NS106875-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9899329. Licensed CC0.

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