A team of international researchers optimized a gene-editing approach to edit the SMN2 gene so that functional SMN protein could be produced from it. They then delivered their “optimized editor” into a mouse model of spinal muscular atrophy (SMA) using adeno-associated virus (AAV) vectors and showed that it was able to precisely edit the SMN2 gene.

“This base editing approach to correct SMN2 should provide a long-lasting genetic treatment for SMA with advantages compared to current nucleic acid, small molecule, or exogenous gene replacement therapies,” the researchers wrote. “More broadly, our work highlights the potential of . . . base editors to install edits efficiently and safely.”

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The study was published in bioRxiv.

The base editor described here turns an A/T dimer into a C/T dimer in exon 7 of the SMN2 gene, thereby ensuring that exon 7 is included in the mature SMN2 messenger RNA (mRNA) and fully functional SMN protein can be produced from the SMN2 gene.

The researchers tested many different base editors and Cas9 enzymes, which led to up to 99% intended editing in fibroblasts derived from patients with SMA and subsequent increases in the expression of SMN2 mRNA including exon 7 and functional SMN protein. 

SMA is caused by a mutation in the SMN1 gene, which results in no functional SMN protein being produced from this gene. 

In humans, there is an additional, highly homologous gene called SMN2, which differs from SMN1 by just a single nucleotide, resulting in an alternative splicing site in exon 7 and reduced SMN protein production.

SMN is essential for the survival of motor neurons, and its deficiency leads to motor neuron loss and the symptoms of SMA. The copy number of the SMN2 gene is inversely correlated with the severity of the disease.


Alves CRR, Ha LL, Yaworski R, et al. Base editing as a genetic treatment for spinal muscular atrophy. bioRxiv. Published online January 21, 2023. doi:10.1101/2023.01.20.524978