阿根廷布宜诺斯艾利斯大学(UBA)Alberto R. Kornblihtt研究组提出，抵消剪接校正反义寡核苷酸 (ASO)的染色质作用可提高其在脊髓性肌萎缩症 (SMA)中的治疗效果。2022年6月9日出版的《细胞》发表了这项成果。

他们表明，通过促进转录延伸，组蛋白去乙酰化酶抑制剂 VPA 与 nusinersen-像 ASO一样促进外显子 7 (E7)包容性。令人惊讶的是，ASO 促进了 SMN2 基因上沉默组蛋白标记 H3K9me2 的部署，从而为抑制 E7 包含的 RNA 聚合酶 II 延伸设置了障碍。通过消除障碍，VPA 抵消了 ASO 的染色质效应，导致更高的 E7 包含而没有大的多效性效应。在SMA小鼠中联合施用 nusinersen 样 ASO 和 VPA 可强烈协同 SMN 表达、生长、存活和神经肌肉功能。

研究人员表示，SMA是一种由 SMN1 基因突变引起的运动神经元疾病。人类旁系同源物SMN2，其E7主要被跳过，不能弥补 SMN1 的缺乏。Nusinersen 是一种ASO，通过将剪接抑制因子 hnRNPA1/A2 从内含子 7 的靶位点置换出来，上调 E7 包含和 SMN 蛋白水平。

附：英文原文

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

Author: Luciano E. Marasco, Gwendal Dujardin, Rui Sousa-Luís, Ying Hsiu Liu, Jose N. Stigliano, Tomoki Nomakuchi, Nick J. Proudfoot, Adrian R. Krainer, Alberto R. Kornblihtt

Issue&Volume: 2022/06/09

Abstract: Spinal muscular atrophy (SMA) is a motor-neuron disease caused by mutations of theSMN1 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 andSMN protein levels by displacing the splicing repressors hnRNPA1/A2 from their targetsite in intron 7. We show that by promoting transcriptional elongation, the histonedeacetylase inhibitor VPA cooperates with a nusinersen-like ASO to promote E7 inclusion.Surprisingly, the ASO promotes the deployment of the silencing histone mark H3K9me2on 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, resultingin higher E7 inclusion without large pleiotropic effects. Combined administrationof the nusinersen-like ASO and VPA in SMA mice strongly synergizes SMN expression,growth, survival, and neuromuscular function.

DOI: 10.1016/j.cell.2022.04.031

Source: https://www.cell.com/cell/fulltext/S0092-8674(22)00529-3