Marasco, Luciano E, Dujardin, Gwendal, Sousa-Luís, Rui, Liu, Ying Hsiu, Stigliano, Jose N, Nomakuchi, Tomoki, Proudfoot, Nick J, Krainer, Adrian R, Kornblihtt, Alberto R (June 2022) Counteracting chromatin effects of a splicing-correcting antisense oligonucleotide improves its therapeutic efficacy in spinal muscular atrophy. Cell, 185 (12). 2057-2070.e15. ISSN 0092-8674
Abstract
Spinal muscular atrophy (SMA) is a motor-neuron disease caused by mutations of the SMN1 gene. The human paralog SMN2, whose exon 7 (E7) is predominantly skipped, cannot compensate for the lack of SMN1. Nusinersen is an antisense oligonucleotide (ASO) that upregulates E7 inclusion and SMN protein levels by displacing the splicing repressors hnRNPA1/A2 from their target site in intron 7. We show that by promoting transcriptional elongation, the histone deacetylase inhibitor VPA cooperates with a nusinersen-like ASO to promote E7 inclusion. Surprisingly, the ASO promotes the deployment of the silencing histone mark H3K9me2 on the SMN2 gene, creating a roadblock to RNA polymerase II elongation that inhibits E7 inclusion. By removing the roadblock, VPA counteracts the chromatin effects of the ASO, resulting in higher E7 inclusion without large pleiotropic effects. Combined administration of the nusinersen-like ASO and VPA in SMA mice strongly synergizes SMN expression, growth, survival, and neuromuscular function.
Item Type: | Paper |
---|---|
Subjects: | diseases & disorders > congenital hereditary genetic diseases > spinal muscular atrophy |
CSHL Authors: | |
Communities: | CSHL labs > Krainer lab |
SWORD Depositor: | CSHL Elements |
Depositing User: | CSHL Elements |
Date: | 9 June 2022 |
Date Deposited: | 24 Jun 2022 16:04 |
Last Modified: | 24 Jun 2022 16:04 |
URI: | https://repository.cshl.edu/id/eprint/40664 |
Actions (login required)
![]() |
Administrator's edit/view item |