Rethinking antisense oligonucleotide therapeutics for amyotrophic lateral sclerosis.

IF 4.4 2区 医学 Q1 CLINICAL NEUROLOGY Annals of Clinical and Translational Neurology Pub Date : 2024-10-29 DOI:10.1002/acn3.52234
Daisuke Ito, Kensuke Okada
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Abstract

Antisense oligonucleotides, which are used to silence target genes, are gaining attention as a novel drug discovery modality for proteinopathies. However, while clinical trials for neurodegenerative diseases like amyotrophic lateral sclerosis have been conducted in recent years, the results have not always been favorable. The results from a Phase III trial of the antisense oligonucleotide, that is, tofersen, which targets SOD1 mRNA, showed decreased levels of cerebrospinal fluid SOD1 and plasma neurofilament light chain but no improvements in primary clinical endpoint. Moreover, case reports pertaining to patients with amyotrophic lateral sclerosis carrying FUS and C9orf72 mutations who received antisense oligonucleotide-based treatments have demonstrated a notable reduction in the targeted protein (thus providing the proof of mechanism) but with no discernible clinical benefits. There are several possible reasons why antisense oligonucleotides knockdown fails to achieve proof of concept, which need to be addressed: on-target adverse effects resulting from the loss of function of target gene and irreversible neuronal death cascade due to toxic protein accumulation, among other factors. This review provides an overview of the current status and discusses the prospects of antisense oligonucleotides treatment for amyotrophic lateral sclerosis.

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反思肌萎缩侧索硬化症的反义寡核苷酸疗法。
反义寡核苷酸可用于抑制靶基因,作为一种治疗蛋白质病的新型药物发现方式,它正受到越来越多的关注。然而,虽然近年来针对肌萎缩侧索硬化症等神经退行性疾病开展了临床试验,但结果并不总是令人满意。针对 SOD1 mRNA 的反义寡核苷酸(即托福森)的 III 期试验结果显示,脑脊液 SOD1 和血浆神经丝轻链的水平有所下降,但主要临床终点没有改善。此外,有关携带 FUS 和 C9orf72 突变的肌萎缩侧索硬化症患者接受反义寡核苷酸治疗的病例报告显示,靶蛋白明显减少(从而提供了机制证明),但没有明显的临床疗效。反义寡核苷酸敲除未能实现概念验证可能有几个原因,需要加以解决:靶基因功能缺失导致的靶向不良反应、毒性蛋白积累导致的不可逆神经元死亡级联等。本综述概述了反义寡核苷酸治疗肌萎缩侧索硬化症的现状并探讨了其前景。
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来源期刊
Annals of Clinical and Translational Neurology
Annals of Clinical and Translational Neurology Medicine-Neurology (clinical)
CiteScore
9.10
自引率
1.90%
发文量
218
审稿时长
8 weeks
期刊介绍: Annals of Clinical and Translational Neurology is a peer-reviewed journal for rapid dissemination of high-quality research related to all areas of neurology. The journal publishes original research and scholarly reviews focused on the mechanisms and treatments of diseases of the nervous system; high-impact topics in neurologic education; and other topics of interest to the clinical neuroscience community.
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