Advances in modeling and treating spinal muscular atrophy Report Summary

Advances in modeling and treating spinal muscular atrophy Report Summary

Author or authors of report : Meaghan Van Alstyne, Livio Pellizzoni
Date of report : 2017-10-01
Spinal Muscular Atrophy (SMA)

Purpose of Review

SMA is an inherited neurodegenerative disorder that manifests in childhood. It is caused by a deficiency of the survival motor neuron (SMN) protein. This deficiency leads to the loss of motor neurons and skeletal muscle atrophy. The article aims to shed light on the recent advancements in understanding SMA pathology and the development of therapeutic approaches.

Recent Findings

Mouse models have been instrumental in understanding the disease. These models, combined with controlled SMN restoration or depletion, have provided insights into the normal requirement of SMN and SMA pathophysiology. There's a higher demand for SMN during neuromuscular development. The effects of SMN deficiency extend beyond motor neurons, affecting other cells within and outside the nervous system. Pre-clinical developments have shown promising approaches to increase SMN expression through gene therapy or splicing modulation. These methods are currently undergoing human trials.


The availability of drugs that upregulate SMN, combined with the identification of specific cell types affected by SMN deficiency, represents significant progress towards SMA therapy.


SMA is a neurodegenerative disorder that affects 1 in 10,000 newborns, making it the leading hereditary cause of infant mortality. It is characterized by the loss of motor neurons in the spinal cord, leading to muscle atrophy, respiratory failure, and, in severe cases, death. The genetic cause of SMA is the homozygous deletion or mutation of the survival motor neuron 1 (SMN1) gene. Another gene, SMN2, produces a truncated form of the protein, which cannot fully compensate for the loss of SMN1, leading to SMA.

Motor System Dysfunction in SMA

Severe SMA mice models show a pronounced loss of motor neurons, a characteristic of the human disease. There are differential susceptibilities of individual motor neuron pools, which correlate with the vulnerability of distinct muscle groups. SMN deficiency induces various pathological changes in the motor circuit, including reduced synaptic vesicle density, decreased neurotransmission, and denervation. These changes are more prominent in vulnerable muscles, correlating with impaired muscle growth. Several central defects have been documented in SMA mice, including the loss of excitatory synapses on motor neurons, leading to increased membrane excitability.

Requirement of SMN

SMN is a ubiquitously expressed protein. The development and characterization of animal models have been fundamental in understanding SMA pathogenesis. The phenotypic characterization of mouse models indicates that motor neurons are the most vulnerable cell types affected by SMN deficiency. However, there's increasing evidence of functional deficits outside the central nervous system.