Spinal muscular atrophy: antisense oligonucleotide therapy opens the door to an integrated therapeutic landscape.

Wood, MJA; Talbot, K; Bowerman, M

Abstract

Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder characterized by loss of spinal cord motor neurons, muscle atrophy and infantile death or severe disability. It is caused by severe reduction of the ubiquitously expressed survival motor neuron (SMN) protein, owing to loss of the SMN1 gene. This would be completely incompatible with survival without the presence of a quasi-identical duplicated gene, SMN2, specific to humans. SMN2 harbours a silent point mutation that favours the production of transcripts lacking exon 7 and a rapidly degraded non-functional SMN?7 protein, but from which functional full length SMN protein is produced at very low levels (~10%). Since the seminal discovery of the SMA-causing gene in 1995, research has focused on the development of various SMN replacement strategies culminating, in December 2016, in the approval of the first precise molecularly targeted therapy for SMA (nusinersen), and a pivotal proof of principle that therapeutic antisense oligonucleotide (ASO) treatment can effectively target the central nervous system (CNS) to treat neurological and neuromuscular disease. Nusinersen is a steric block ASO that binds the SMN2 messenger RNA and promotes exon 7 inclusion and thus increases full length SMN expression. Here, we consider the implications of this therapeutic landmark for SMA therapeutics and discuss how future developments will need to address the challenges of delivering ASO therapies to the CNS, with appropriate efficiency and activity, and how SMN-based therapy should be used in combination with complementary strategies to provide an integrated approach to treat CNS and peripheral pathologies in SMA.

Citation

Wood, M., Talbot, K., & Bowerman, M. (2017). Spinal muscular atrophy: antisense oligonucleotide therapy opens the door to an integrated therapeutic landscape. Human molecular genetics, 26(R2), R151 - R159. https://doi.org/10.1093/hmg/ddx215

• Journal Article Type: Article
• Acceptance Date: Jun 2, 2017
• Online Publication Date: Jun 13, 2017
• Publication Date: Oct 1, 2017
• Publicly Available Date: May 26, 2023
• Journal: Human Molecular Genetics
• Print ISSN: 1460-2083
• Electronic ISSN: 1460-2083
• Publisher: Oxford University Press
• Peer Reviewed: Peer Reviewed
• Volume: 26
• Issue: R2
• Pages: R151 - R159
• DOI: https://doi.org/10.1093/hmg/ddx215
• Keywords: neuromuscular disease; antisense oligonucleotides; central nervous system; exons; genes; motor neurons; muscular atrophy; spinal muscular atrophy; point mutation; rna; messenger; spinal cord; antisense oligonucleotide therapy; smn1 protein; molecular targ
• Publisher URL: https://academic.oup.com/hmg/article/26/R2/R151/3867126