ASOs for spinal muscular atrophy

In the new paper scientists from Isis Pharmaceuticals report on the development of the new mouse model for spinal muscular atrophy types I and II. The disease emerges from corrupted splicing of the SMN genes. The problem with previous models was that they were either too severe (with complete knockout of the ‘good’ protein), or too mild. So authors attempted to balance the copy number of the protein and create an ‘intermediate’ mouse line. They achieved that by combining ‘mild’ and ‘severe’ alleles and inserting additional human SMN2 gene into corresponding murine locus. So the resulting mice could live long enough and develop the expected neuromuscular pathology with relatively late onset of sympoms.

What’s more exciting is that when mutant mice were treated with the antisense oligo (ASO) targeting the pre-mRNA of SMN2 gene, the lethality and symptoms were improved. Even more surprising was the finding that delivery of the drug into CNS was not required for the improvement. The question remains if this feature translates into patients. Potentially this can lead to better understanding of the SMA pathology, namely if the disease originates in muscles or in neurons and what are the feedback loops between two cell types.