Expansions of a G₄C₂ repeat in the C9ORF72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two devastating adult-onset neurodegenerative disorders. Using C9-ALS/FTD patient-derived cells and C9ORF72 BAC transgenic mice, we generated and optimized antisense oligonucleotides (ASOs) that selectively blunt expression of G₄C₂ repeat-containing transcripts and effectively suppress tissue levels of poly(GP) dipeptides. ASOs with reduced phosphorothioate content showed improved tolerability without sacrificing efficacy. In a single patient harboring mutant C9ORF72 with the G₄C₂ repeat expansion, repeated dosing by intrathecal delivery of the optimal ASO was well tolerated, leading to significant reductions in levels of cerebrospinal fluid poly(GP). This report provides insight into the effect of nucleic acid chemistry on toxicity and, to our knowledge, for the first time demonstrates the feasibility of clinical suppression of the C9ORF72 gene. Additional clinical trials will be required to demonstrate safety and efficacy of this therapy in patients with C9ORF72 gene mutations.

C9ORF72基因中 G ₄ C ₂重复序列的扩展是肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆 (FTD) 这两种毁灭性成人发病的神经退行性疾病的最常见遗传原因。使用 C9-ALS/FTD 患者来源的细胞和C9ORF72 BAC 转基因小鼠，我们生成并优化了反义寡核苷酸 (ASO)，可选择性减弱含有 G ₄ C ₂重复序列的转录物的表达，并有效抑制聚 (GP) 二肽的组织水平。硫代磷酸酯含量降低的 ASO 在不牺牲功效的情况下表现出更好的耐受性。在一名携带​​具有 G ₄ C ₂重复扩增的突变体C9ORF72的患者中，通过鞘内递送最佳 ASO 进行重复给药具有良好的耐受性，导致脑脊液聚 (GP) 水平显着降低。该报告深入了解了核酸化学对毒性的影响，据我们所知，该报告首次证明了临床抑制C9ORF72基因的可行性。需要进行更多的临床试验来证明这种疗法对C9ORF72基因突变患者的安全性和有效性。