Targeting the 5' untranslated region of SMN2 as a therapeutic strategy for spinal muscular atrophy
Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by mutations in the survival motor neuron 1 (<i>SMN2</i>) gene. All patients have at least one copy of a paralog, <i>SMN2</i>, but a C-to-T transition in this gene results in exon 7 skipping in a majority of tra...
| Main Authors: | , , , , , , , , , , , |
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| 格式: | Journal article |
| 語言: | English |
| 出版: |
Cell Press
2021
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| 總結: | Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by mutations in the survival motor neuron 1 (<i>SMN2</i>) gene. All patients have at least one copy of a paralog, <i>SMN2</i>, 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 <i>SMN2</i> transcript or increasing the amount of full-length SMN by gene replacement with a viral vector. Increasing the pool of <i>SMN2</i> 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 <i>SMN2</i> contains a repressive feature that can be targeted to increase SMN levels. We found that antisense oligonucleotides (ASOs) complementary to the 5' end of <i>SMN2</i> increase SMN mRNA and protein levels and that this effect is due to inhibition of <i>SMN2</i> 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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