DNA-based therapeutics have emerged as a revolutionary approach for addressing the treatment gap in rare inherited conditions by targeting the fundamental genetic causes of disease. Charcot-Marie-Tooth (CMT) disease, a group of inherited neuropathies, represents one of the most prevalent Mendelian disease groups in neurology and is characterized by diverse genetic etiology. Axonal forms of CMT, known as CMT2, are caused by dominant mutations in over 30 different genes which lead to degeneration of lower motor neuron axons. Recent advances in antisense oligonucleotide (ASO) therapeutics have shown promise in targeting neurodegenerative disorders. Here we elucidate pathomechanistic changes contributing to variant specific molecular phenotypes in CMT2E, caused by a single nucleotide substitution (p.N98S) in the neurofilament light chain gene (NEFL). We used a patient-derived pluripotent stem cell (iPSC)-induced motor neuron model, which recapitulates several cellular and biomarker phenotypes associated with CMT2E. Using an ASO treatment strategy targeting a heterozygous gain-of-function variant, we aimed to resolve molecular phenotypic changes observed in the CMT2E p.N98S subtype. To determine ASO therapeutic potential, we employed our treatment strategy in iPSC-derived motor neurons and used established as well as novel biomarkers of peripheral nervous system axonal degeneration. Our findings have demonstrated a significant decrease in clinically relevant biomarkers of axonal degeneration, presenting the first clinically viable genetic therapeutic for CMT2E. Similar strategies could be used to develop precision medicine approaches for otherwise untreatable gain of function inherited disorders.

中文翻译：

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基于反义寡核苷酸的定制治疗神经丝相关夏科-马里-图思病


基于 DNA 的疗法已成为一种革命性方法，通过针对疾病的基本遗传原因来解决罕见遗传性疾病的治疗缺口。腓骨肌萎缩症 (CMT) 是一组遗传性神经病，代表神经病学中最常见的孟德尔疾病组之一，其特点是具有多种遗传病因。轴突形式的 CMT（称为 CMT2）是由 30 多个不同基因的显性突变引起的，这些突变会导致下运动神经元轴突变性。反义寡核苷酸（ASO）疗法的最新进展显示出针对神经退行性疾病的前景。在这里，我们阐明了导致 CMT2E 变异特定分子表型的病理机制变化，这是由神经丝轻链基因 (NEFL) 中的单核苷酸替换 (p.N98S) 引起的。我们使用患者来源的多能干细胞 (iPSC) 诱导的运动神经元模型，该模型概括了与 CMT2E 相关的几种细胞和生物标志物表型。使用针对杂合功能获得变异的 ASO 治疗策略，我们旨在解决在 CMT2E p.N98S 亚型中观察到的分子表型变化。为了确定 ASO 的治疗潜力，我们在 iPSC 衍生的运动神经元中采用了我们的治疗策略，并使用了周围神经系统轴突变性的已建立的和新型的生物标志物。我们的研究结果表明轴突变性的临床相关生物标志物显着减少，提出了第一个临床上可行的 CMT2E 基因疗法。类似的策略可用于开发精准医学方法，以治疗无法治疗的功能获得性遗传性疾病。