Antisense oligonucleotide mediated therapy of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality. SMA results from deletions or mutations of (), an essential gene. , a nearly identical copy, can compensate for loss if exon 7 skipping is prevented. Among the many cis-elements involved in the splicing regulation of exon 7, intronic splicing silencer N1 (ISS-N1) has emerged as the most effective target for an antisense oligonucleotide (ASO)-mediated splicing correction of exon 7. Blocking of ISS-N1 by an ASO has been shown to fully restore exon 7 inclusion in SMA patient cells as well as in vivo. Here we review how ISS-N1 targeting ASOs that use different chemistries respond differently in the various SMA mouse models. We also compare other ASO-based strategies for therapeutic splicing correction in SMA. Given that substantial progress on ASO-based strategies to promote exon 7 inclusion in SMA has been made, and that similar approaches in a growing number of genetic diseases are possible, this report has wide implications.