The most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD) is an expanded G₄C₂ RNA repeat [r(G₄C₂)^exp] in chromosome 9 open reading frame 72 (C9orf72), which elicits pathology through several mechanisms. Here, we developed and characterized a small molecule for targeted degradation of r(G₄C₂)^exp. The compound was able to selectively bind r(G₄C₂)^exp’s structure and to assemble an endogenous nuclease onto the target, provoking removal of the transcript by native RNA quality control mechanisms. In c9ALS patient–derived spinal neurons, the compound selectively degraded the mutant C9orf72 allele with limited off-targets and reduced quantities of toxic dipeptide repeat proteins (DPRs) translated from r(G₄C₂)^exp. In vivo work in a rodent model showed that abundance of both the mutant allele harboring the repeat expansion and DPRs were selectively reduced by this compound. These results demonstrate that targeted small-molecule degradation of r(G₄C₂)^exp is a strategy for mitigating c9ALS/FTD-associated pathologies and studying disease-associated pathways in preclinical models.

中文翻译：

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使用小分子募集核糖核酸酶可减少体外和体内 ALS 模型中的 c9ALS/FTD r(G4C2) 重复扩增

肌萎缩侧索硬化和额颞叶痴呆 (c9ALS/FTD) 的最常见原因是第 9 号染色体开放阅读框 72 ( C9orf72 )中的 G ₄ C ₂ RNA 重复序列 [r(G ₄ C ₂ ) ^exp ]几种机制。在这里，我们开发并表征了一种用于靶向降解 r(G ₄ C ₂ ) ^exp的小分子。该化合物能够选择性地结合 r(G ₄ C ₂ ) ^exp的结构并将内源性核酸酶组装到靶标上，从​​而通过天然 RNA 质量控制机制去除转录本。在 c9ALS 患者衍生的脊髓神经元中，该化合物选择性地降解突变C9orf72等位基因，具有有限的脱靶和减少从 r(G ₄ C ₂ ) ^exp翻译的有毒二肽重复蛋白 (DPR) 的数量。在啮齿动物模型中的体内研究表明，这种化合物选择性地降低了具有重复扩增和 DPR 的突变等位基因的丰度。这些结果表明，r(G ₄ C ₂ ) ^{exp的靶向小分子降解}是一种在临床前模型中减轻 c9ALS/FTD 相关病理和研究疾病相关途径的策略。