Written by Fazil Hussein: SMA base editing, or base editing implementation for treatment of spinal muscular atrophy, was successful in cell and mouse models according to a recent article.

Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality. It is a rare neuromuscular disorder that results in the loss of motor neurons and progressive muscle wasting. There is a missing or nonworking survival motor neuron 1 (SMN1) gene. This gene tells motor neuron cells to produce survival motor neuron (SMN) protein. When motor neuron cells don’t get enough SMN protein, they stop working. This means everyday activities like eating, breathing, or sitting up become harder to do, and can be lost permanently. Gene therapy was previously described for this disease. Drawbacks for this therapy included the high cost and the serious side effects.

 

Base editing couples a Cas9 protein that only cuts one strand of DNA to another enzyme that chemically converts one DNA base to another. The Cas9 directs the base-editing enzyme to the right location in the genome; the other enzyme then acts on that site, ideally producing only one edit.

 

How SMA base editing works

The researchers targeted SMN2, not SMN1 gene. SMN2 differs from SMN1 at just one position—a single C-to-T mutation in exon 7. The result is a defective truncated SMN protein that fails to fully compensate for the loss of SMN1, but which provides just enough SMN protein activity to allow babies to be born with SMA. Base editing converted SMN2 to the same sequence as SMN1 by reversing the C-to-T mutation, thus restoring SMN protein levels to wild-type.

 

Implications of the SMA base editing study

The findings of this study demonstrate the potential of a one-time SMA base editing treatment to permanently restore SMN protein levels and rescue SMA phenotypes. The SMN2 base editing approach could potentially be applied to all SMA patients regardless of the specific mutation that caused their SMN1 loss because it does not target their specific SMN1 mutation, but instead corrects the defective duplicated copy of SMN that they all possess.

Such an approach of converting imperfectly duplicated or cryptic genes, using precise gene editing technologies, into healthy genes may also be a viable strategy to treat other genetic diseases.

 

 

Sources:

Base editing rescue of spinal muscular atrophy in cells and in mice.

One-Time Treatment: Base Editing Shows Promise vs. SMA.

 

 

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