RNA in spinal muscular atrophy: therapeutic implications of targeting

Spinal muscular atrophy (SMA) is caused by low levels of the Survival Motor Neuron (SMN) protein due to deletions of or mutations in the gene. Humans carry another nearly identical gene, , which mostly produces a truncated and less stable protein SMNΔ7 due to predominant skipping of exon 7. Elevatio...

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Bibliographic Details
Published in:	Expert opinion on therapeutic targets Vol. 24; no. 8; p. 731
Main Authors:	Singh, Ravindra N, Seo, Joonbae, Singh, Natalia N
Format:	Journal Article
Language:	English
Published:	England 02-08-2020
Subjects:	Animals Exons Genetic Therapy - methods Humans Molecular Targeted Therapy Muscular Atrophy, Spinal - genetics Muscular Atrophy, Spinal - therapy Mutation RNA - genetics RNA Splicing - genetics Survival of Motor Neuron 1 Protein - genetics Survival of Motor Neuron 2 Protein - genetics SpinrazaTM Survival Motor Neuron RNP SMN SMA circular RNA nusinersen ISS-N1 Spinal muscular atrophy antisense pre-mRNA splicing
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Summary:	Spinal muscular atrophy (SMA) is caused by low levels of the Survival Motor Neuron (SMN) protein due to deletions of or mutations in the gene. Humans carry another nearly identical gene, , which mostly produces a truncated and less stable protein SMNΔ7 due to predominant skipping of exon 7. Elevation of SMN upon correction of exon 7 splicing and gene therapy have been proven to be the effective treatment strategies for SMA. This review summarizes existing and potential SMA therapies that are based on RNA targeting.We also discuss the mechanistic basis of RNA-targeting molecules. 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.
ISSN:	1744-7631
DOI:	10.1080/14728222.2020.1783241