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...
| Autores principales: | , , , , , , , , , , , |
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| Formato: | Journal article |
| Lenguaje: | English |
| Publicado: |
Cell Press
2021
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| _version_ | 1826306717575544832 |
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| author | Winkelsas, AM Grunseich, C Harmison, GG Chwalenia, K Rinaldi, C Hammond, SM Johnson, K Bowerman, M Arya, S Talbot, K Wood, MJ Fischbeck, KH |
| author_facet | Winkelsas, AM Grunseich, C Harmison, GG Chwalenia, K Rinaldi, C Hammond, SM Johnson, K Bowerman, M Arya, S Talbot, K Wood, MJ Fischbeck, KH |
| author_sort | Winkelsas, AM |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T06:52:11Z |
| format | Journal article |
| id | oxford-uuid:fce8de4a-836e-4fd1-bbec-6bf1a48beedc |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:52:11Z |
| publishDate | 2021 |
| publisher | Cell Press |
| record_format | dspace |
| spelling | oxford-uuid:fce8de4a-836e-4fd1-bbec-6bf1a48beedc2022-03-27T13:24:50ZTargeting the 5' untranslated region of SMN2 as a therapeutic strategy for spinal muscular atrophyJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:fce8de4a-836e-4fd1-bbec-6bf1a48beedcEnglishSymplectic ElementsCell Press2021Winkelsas, AMGrunseich, CHarmison, GGChwalenia, KRinaldi, CHammond, SMJohnson, KBowerman, MArya, STalbot, KWood, MJFischbeck, KHSpinal 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. |
| spellingShingle | Winkelsas, AM Grunseich, C Harmison, GG Chwalenia, K Rinaldi, C Hammond, SM Johnson, K Bowerman, M Arya, S Talbot, K Wood, MJ Fischbeck, KH Targeting the 5' untranslated region of SMN2 as a therapeutic strategy for spinal muscular atrophy |
| title | Targeting the 5' untranslated region of SMN2 as a therapeutic strategy for spinal muscular atrophy |
| title_full | Targeting the 5' untranslated region of SMN2 as a therapeutic strategy for spinal muscular atrophy |
| title_fullStr | Targeting the 5' untranslated region of SMN2 as a therapeutic strategy for spinal muscular atrophy |
| title_full_unstemmed | Targeting the 5' untranslated region of SMN2 as a therapeutic strategy for spinal muscular atrophy |
| title_short | Targeting the 5' untranslated region of SMN2 as a therapeutic strategy for spinal muscular atrophy |
| title_sort | targeting the 5 untranslated region of smn2 as a therapeutic strategy for spinal muscular atrophy |
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