A short antisense oligonucleotide ameliorates symptoms of severe mouse models of spinal muscular atrophy

Jeffrey M. Keil; Joonbae Seo; Matthew D. Howell; Walter H. Hsu; Ravindra N. Singh; Christine J. DiDonato

doi:10.1038/mtna.2014.23

A short antisense oligonucleotide ameliorates symptoms of severe mouse models of spinal muscular atrophy

Jeffrey M. Keil, Joonbae Seo, Matthew D. Howell, Walter H. Hsu, Ravindra N. Singh^*, Christine J. DiDonato

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

47 Scopus citations

Abstract

Recent reports underscore the unparalleled potential of antisense-oligonucleotide (ASO)-based approaches to ameliorate various pathological conditions. However, in vivo studies validating the effectiveness of a short ASO (<10-mer) in the context of a human disease have not been performed. One disease with proven amenability to ASO-based therapy is spinal muscular atrophy (SMA). SMA is a neuromuscular disease caused by loss-of-function mutations in the survival motor neuron 1 (SMN1) gene. Correction of aberrant splicing of the remaining paralog, SMN2, can rescue mouse models of SMA. Here, we report the therapeutic efficacy of an 8-mer ASO (3UP8i) in two severe models of SMA. While 3UP8i modestly improved survival and function in the more severe Taiwanese SMA model, it dramatically increased survival, improved neuromuscular junction pathology, and tempered cardiac deficits in a new, less severe model of SMA. Our results expand the repertoire of ASO-based compounds for SMA therapy, and for the first time, demonstrate the in vivo efficacy of a short ASO in the context of a human disease.

Original language	English (US)
Article number	e174
Pages (from-to)	e174
Journal	Molecular Therapy Nucleic Acids
Volume	3
DOIs	https://doi.org/10.1038/mtna.2014.23
State	Published - Jul 1 2014

Funding

This work was supported in part by grants from National Institutes of Health (NIH) (NS072259 and NS055925) and Salsbury Endowment to Ravindra Singh (Iowa State University, Ames, IA), and NIH R01NS060926, the Families of SMA (DID1214) and Muscular Dystrophy Association (255785) to Christine DiDonato (Manne Children's Research Institute, Chicago, IL). GCRS target (Patent# US 20110269820 A1) was discovered at Iowa State University. Therefore, inventors including RNS and Iowa State University could potentially benefit from commercial exploitation of GCRS target.

Keywords

Antisense oligonucleotide
Cardiac
SMA mouse model
SMN2
Short ASO
Skeletal muscle
Spinal muscular atrophy
Splicing

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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10.1038/mtna.2014.23

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title = "A short antisense oligonucleotide ameliorates symptoms of severe mouse models of spinal muscular atrophy",

abstract = "Recent reports underscore the unparalleled potential of antisense-oligonucleotide (ASO)-based approaches to ameliorate various pathological conditions. However, in vivo studies validating the effectiveness of a short ASO (<10-mer) in the context of a human disease have not been performed. One disease with proven amenability to ASO-based therapy is spinal muscular atrophy (SMA). SMA is a neuromuscular disease caused by loss-of-function mutations in the survival motor neuron 1 (SMN1) gene. Correction of aberrant splicing of the remaining paralog, SMN2, can rescue mouse models of SMA. Here, we report the therapeutic efficacy of an 8-mer ASO (3UP8i) in two severe models of SMA. While 3UP8i modestly improved survival and function in the more severe Taiwanese SMA model, it dramatically increased survival, improved neuromuscular junction pathology, and tempered cardiac deficits in a new, less severe model of SMA. Our results expand the repertoire of ASO-based compounds for SMA therapy, and for the first time, demonstrate the in vivo efficacy of a short ASO in the context of a human disease.",

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A short antisense oligonucleotide ameliorates symptoms of severe mouse models of spinal muscular atrophy

Abstract

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Keywords

ASJC Scopus subject areas

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