# Spinal muscular atrophy: Mechanisms & treatment strategies.

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $396,649

## Abstract

Project Summary
Spinal muscular atrophy (SMA) is a common, frequently fatal, neuromuscular disorder caused by mutations in
the Survival of Motor Neuron 1 (SMN1) gene and, consequently, a paucity of the SMN protein. In humans, an
almost identical copy gene, SMN2, is unable to fully compensate for loss of SMN1 owing to a splicing defect
and thus an inability to express sufficient protein to stave off disease. In the two decades that we have
researched SMA much progress has been made, from the identification of the disease gene and the
description of its protein to the generation of pre-clinical models and, most recently, the approval of Spinraza, a
promising drug that raises SMN levels and thus thwarts the inevitable paralysis and frequent death associated
with SMA. While Spinraza, in particular, raises considerable optimism for SMA patients, significant challenges
remain and, in our minds, stem from two crucial deficiencies. First, despite the milestones achieved, how low
SMN protein evolves into the SMA phenotype, selectively triggering motor neuron death and preferentially
disabling the neuromuscular system remains a singular mystery. This is especially perplexing considering
SMN's most widely-cited function of orchestrating the splicing cascade. Identifying mediators that provide a
logical explanation for why splicing defects cause SMA or, uncovering additional, more disease-relevant SMN
functions is therefore not only mechanistically but also therapeutically relevant. Second, while it is clear that
administering Spinraza provides immediate benefit to patients, it is premature to make a determination of the
long-term outcome of such treatment; the drug is selectively delivered to the CNS, raising questions about the
effects of chronic low SMN in the periphery. Besides, the strategy of raising SMN appears inadequate in the
symptomatic patient. Here we describe 3 related sets of experiments that address the deficiencies identified
above. Aim 1 proposes to define disease-relevant mechanisms by exploiting a novel line of SMA mice in
which early mortality, motor neuron loss and a severe phenotype are replaced by prolonged survival, intact
motor neurons and a decidedly mild phenotype. We hypothesize that a spontaneous mutation in a chaperone
protein that the mice express suppresses the SMA phenotype. We will confirm and extend this finding to
determine how the chaperone modulates the effects of low SMN. In aim 2, we will examine the potential long-
term adverse effects of persistently low levels of SMN in muscles of model mice expressing normal protein in
the CNS. Such rodents represent a pre-clinical model of SMA patients administered Spinraza. We propose
that chronic low SMN in skeletal muscle has a profoundly negative impact on the health of the tissue and
contributes to the overall SMA phenotype. In aim 3, we will determine if the disease-causing effects of low
SMN in muscle can nevertheless be mitigated upon restoring protein post-symptomaticall...

## Key facts

- **NIH application ID:** 10308474
- **Project number:** 5R01NS104218-04
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Umrao Monani
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $396,649
- **Award type:** 5
- **Project period:** 2018-12-15 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10308474

## Citation

> US National Institutes of Health, RePORTER application 10308474, Spinal muscular atrophy: Mechanisms & treatment strategies. (5R01NS104218-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10308474. Licensed CC0.

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