RNA in spinal muscular atrophy: therapeutic implications of targeting

Introduction Spinal muscular atrophy (SMA) is caused by low levels of the Survival Motor Neuron (SMN) protein due to deletions of or mutations in theSMN1gene. Humans carry another nearly identical gene,SMN2, which mostly produces a truncated and less stable protein SMN Delta 7 due to predominant skipping of exon 7. Elevation of SMN upon correction ofSMN2exon 7 splicing and gene therapy have been proven to be the effective treatment strategies for SMA. Areas covered This review summarizes existing and potential SMA therapies that are based on RNA targeting.We also discuss the mechanistic basis of RNA-targeting molecules. Expert opinion The discovery of intronic splicing silencer N1 (ISS-N1) was the first major step towards developing the currently approved antisense-oligonucleotide (ASO)-directed therapy (SpinrazaTM) based on the correction of exon 7 splicing of the endogenous SMN2pre-mRNA. Recently, gene therapy (Zolgensma) has become the second approved treatment for SMA. Small compounds (currently in clinical trials) capable of restoring SMN2 exon 7 inclusion further expand the class of the RNA targeting molecules for SMA therapy. Endogenous RNA targets, such as long non-coding RNAs, circular RNAs, microRNAs and ribonucleoproteins, could be potentially exploited for developing additional SMA therapies.