Targeting the 5′ untranslated region of SMN2 as a therapeutic strategy for spinal muscular atrophy

• Published in: Molecular therapy. Nucleic acids Vol. 23; pp. 731 - 742
• Main Authors: Winkelsas, Audrey M., Grunseich, Christopher, Harmison, George G., Chwalenia, Katarzyna, Rinaldi, Carlo, Hammond, Suzan M., Johnson, Kory, Bowerman, Melissa, Arya, Sukrat, Talbot, Kevin, Wood, Matthew J., Fischbeck, Kenneth H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05-03-2021; American Society of Gene & Cell Therapy; Elsevier
• Subjects: 5′ UTR; antisense oligonucleotides; Original; SMN2; spinal muscular atrophy; SMN2; 5′ UTR; spinal muscular atrophy; antisense oligonucleotides
• ISSN: 2162-2531; 2162-2531
• DOI: 10.1016/j.omtn.2020.12.027

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by mutations in the survival motor neuron 1 (SMN1) gene. 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, use of 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.
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Spinal muscular atrophy (SMA) is caused by SMN protein deficiency. Winkelsas et al. show that antisense oligonucleotides complementary to the 5′ end of SMN transcripts increase SMN protein levels by stabilizing SMN mRNA. In cells, this strategy can be used in combination with splice-switching oligonucleotides (i.e., nusinersen) for SMA treatment.