Counteracting chromatin effects of a splicing-correcting antisense oligonucleotide improves its therapeutic efficacy in spinal muscular atrophy

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:	Nomakuchi, Tomoki Krainer, Adrian R. Liu, Ying Hsiu
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

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