A Big Step Forward for Spinal Muscular Atrophy?


Potential approaches to devising strategies that may allow amelioration of this disease are revealed in a recent study. But questions remain.

Developmental forms of motor neuron disease usually are disastrous syndromes that frequently lead to early demise of children due to loss of spinal motor neurons and generalized paralysis. The most common genetic spinal muscular atrophy (SMA) form is caused by altering the dosage of 2 genes, SMN1 and SMN2. The genetics are complicated by the fact that the SMN2 gene is expressed widely but at low levels so that loss of the SMN1 gene is compatible with early embryonic development while in other species deletion of SMN1 is early lethal (because of the lack of the partially compensating effects of SMN2).

This has made it challenging to develop adequate models to devise possible treatment strategies. However, a recent study1 in the Annals of Neurology has provided an important step forward and revealed potential approaches that may allow amelioration of this disease at some point in the future.

The key to this new model was to develop an approach that allows decreasing the dosage of the SMN protein in motor neurons in a selective way. The authors used adeno-associated viruses to knock down expression of SMN (using shRNA constructs) in early postnatal piglets and found that this leads to decreased protein expression that is in the same range as that seen in human patients with SMA.

This led to a clinical syndrome in the pigs over the following weeks that closely resembled that seen in patients with SMA. The pigs developed evidence of denervation and motor weakness accompanying pathologic loss of motor neurons. Thus, this appears to be a fairly faithful model of SMA in a large animal.

The authors went on to show that if they first infected the piglets with a virus that expresses human SMN (and that doesn’t get knocked down by the shRNAs), the clinical syndrome could be prevented in the piglets infected with shRNA viruses. This demonstrates that indeed it is the knockdown of SMN in the piglets that is responsible for the clinical syndrome.

More importantly and of potential relevance in patients, the investigators went on to rescue the piglets after the onset of clinical symptoms by expressing human SMN after the induction of the syndrome and showing that this is able to at least partially correct the phenotype-clinically, pathologically, and electrophysiologically.

This study raises reasonable hope that a virus-based expression approach could meaningfully correct the molecular phenotype in patients with severe forms of SMA and perhaps convert their phenotype to less severe SMA phenotypes.

Obviously, many questions remain after this fairly early stage study:

• How long can this correction be made to last?

• In this study, the authors found clear clinical improvement that lasted for a month or 2, but would it be permanent or would repeated treatments to boost expression be necessary?

• Will adeno-associated viruses be the best choice for this approach?

Although this virus-mediated molecular treatment approach may seem extreme, I think that in the context of such a dire disease as severe SMA this type of approach may well find significant traction.


1. Duque SI, Arnold WD, Odermatt P, et al. A large animal model of spinal muscular atrophy and correction of phenotype. Ann Neurol. 2015;77:399-414.

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