Winkelsas, AM, Grunseich, C, Harmison, GG, Chwalenia, K, Rinaldi, C, Hammond, SM, Johnson, K, Bowerman, M, Arya, S, Talbot, K, Wood, MJ and Fischbeck, KH (2021) Targeting the 5’ untranslated region of SMN2 as a therapeutic strategy for spinal muscular atrophy. Molecular Therapy: Nucleic Acids, 23. pp. 731-742. ISSN 2162-2531

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Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by mutations in the survival motor neuron 1 gene (SMN1). All patients have at least one copy of a paralog, SMN2, but a C-to-T transition in this gene results in exon 7 skipping in a majority of transcripts. Approved treatment for SMA involves promoting exon 7 inclusion in the SMN2 transcript or increasing the amount of full-length SMN by gene replacement with a viral vector. Increasing the pool of SMN2 transcripts and increasing their translational efficiency can be used to enhance splice correction. We sought to determine whether the 5’ untranslated region (5’UTR) of SMN2 contains a repressive feature that can be targeted to increase SMN levels. We found that antisense oligonucleotides (ASOs) complementary to the 5’ end of SMN2 increase SMN mRNA and protein levels, and that this effect is due to inhibition of SMN2 mRNA decay. Moreover, using the 5’UTR ASO in combination with a splice-switching oligonucleotide (SSO) increases SMN levels above those attained with the SSO alone. Our results add to the current understanding of SMN regulation and point toward a new therapeutic target for SMA.

Item Type: Article
Additional Information: The final version of this article and all relevant information related to it can be found online at;
Uncontrolled Keywords: antisense oligonucleotides spinal muscular atrophy 5′ UTR SMN2
Subjects: R Medicine > R Medicine (General)
R Medicine > RC Internal medicine > RC925 Diseases of the musculoskeletal system
Divisions: Faculty of Medicine and Health Sciences > School of Medicine
Depositing User: Symplectic
Date Deposited: 03 Jan 2021 22:51
Last Modified: 14 Apr 2021 14:40

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