Orally bioavailable small molecules that target RNA and RNA related processes have a delivery and distribution advantage over oligonucleotides. However, targeting specific RNA sequences or structures with small molecules remains a significant challenge. We have recently reported success in shifting <i>SMN2</i> pre-mRNA splicing to include exon 7, thus increasing levels of full length SMN protein in SMA patient derived cells. Chemical optimization of these molecules has yielded compounds that increase SMN protein and ameliorate disease phenotype in mouse models of SMA. Two optimized compounds have advanced to human clinical trials and have demonstrated a dose-dependent effect on <i>SMN2</i> splicing and SMN protein increase in humans. These molecules exhibit remarkable selectivity, targeting a small set of specific sequences located at the 5' splice site of pre-mRNA. Recent discoveries have led to a better understanding of the sequence determinants for pharmacologic splicing modulation and have facilitated the development of structure selectivity relationships.

To splice or not to splice: Can small molecules answer the question?

255th National Meeting (2018)

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