Therapy Restores Function in Mice with Spinal Muscular Atrophy

Rebekah Harrison

Jackson Laboratory (JAX) researchers have tested a therapeutic intervention for spinal muscular atrophy (SMA) that restores some function lost due to a mutation in one gene (SMN1) and amplifies the levels of protective genes (SMN2).1
According to a press release, the therapy appears to work after symptoms of SMA have already appeared, and may not need to be administered directly into the central nervous system.

What is Spinal Muscular Atrophy?

Spinal muscular atrophy (SMA) is a genetic neuropathy. It is caused by the loss of motor neurons in the spinal cord due to mutations of the SMN1 gene. Affected individuals usually experience mild to moderate muscle weakness, tremor, twitching, or mild breathing problems. Typically, muscles close to the proximal muscles, such as the upper arms and legs, are most affected. 2
According to Jackson Laboratory, SMA is difficult to model in mice. Current mouse models expressing small amounts of SMN protein die by about 2 weeks of age however, increasing this protein level by just a small amount renders the mice almost normal. This makes therapy testing very difficult and doesn't model the symptoms or processes associated with the less severe types of the disease.
the research group led by Cat Lutz, Ph.D., director of the JAX Rare and Orphan Disease Center, is working to improve the ability to model SMA in mice.
As published on October 12 in the Proceedings of the National Academy of Sciences, the research group’s first step was to genetically engineer mouse models with increasing copy numbers of human SMN2. Through this work, they were able to develop a mouse model with very mild neuromuscular defects that lives a near normal life span, and little motor neuron denervation.
The researchers developed a model with SMN1, human SMN2 and a third allele (dubbed the C allele) that combines parts of mouse SMN with parts of human SMN2. This combination produced a mouse that had a relatively long life span compared to severe mutants (about 100 days) combined with SMA-like neuromuscular disease phenotype.
The new model allowed Lutz and her colleagues to test a current therapeutic intervention that restores SMN levels and has a significant effect in severe models. The therapy, known as an antisense oligonucleotide, worked to restore SMN levels in the new model and injections 25 days after symptoms had begun increased life span and restored motor unit function in the muscles.
"The majority of the preclinical data that we have to date comes from type I animal models and suggests that early intervention in the treatment of SMA is necessary," says Lutz. "However, we really don't have good preclinical data that supports whether this is also true for type II/III patients, who represent the majority of patients living with SMA. Our data indicate that post-symptomatic treatment, well into the disease state in mice, has a clinically relevant therapeutic benefit."
Human trials for therapeutics involving antisense oligonucleotides are delivered directly into the central nervous system (CNS). Peripheral application in the mouse model had benefits at the neuromuscular junction, raising the question of what might be alternative delivery mechanisms in humans.
"The benefit may not be restricted to CNS delivery," says Lutz, "which opens up a whole new potential class of compounds and possibilities for combination therapies. Further study in humans will be needed, but the prospect of non-CNS delivery is of significant potential benefit for patients."


1. Treatment restores some function in animal models of spinal muscular atrophy [news release]. Bar Harbor, ME; Jackson Laboratory: October 14, 2015.
2. Spinal muscular atrophy; Genetics Home Reference. January 13, 2013.

Image Courtesy of Wikimedia Commons
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