2020 Volume 37 Issue 3 Pages 247-250
Loss–of–function mutations in SMN1 cause spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. Humans have a closely related SMN2, but it only expresses low levels of SMN protein, due to alternative splicing of exon 7. Antisense oligonucleotides (ASOs) can be designed to regulate splicing of target pre–mRNAs. Based on an ASO–tiling method, we succeeded in identifying an optimized 2′–MOE phosphorothioate ASO that efficiently redirects SMN2 splicing. Its therapeutic efficacy, safety, and pharmacokinetics were proven in preclinical studies using mice and NHPs and further supported by clinical trials in SMA infants and children. Exploring of the in vivo spatial and temporal ASO effects yields insights into SMN roles in SMA pathogenesis, which in turn contributes to the successful development of targeted therapeutics.
