期刊
NATURE MEDICINE
卷 28, 期 1, 页码 117-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41591-021-01557-6
关键词
-
资金
- National Institutes of Health [R01 NS111990]
- Angel Fund for ALS Research
- Ono Pharmaceutical Foundation
- ALSOne
- ALS Finding a Cure
- Cellucci Fund for ALS Research
- Max Rosenfeld Fund
- University of Massachusetts Clinical and Translational Science Award from the National Center for Advancing Translational Sciences of the National Institutes of Health [UL1TR001453]
The study successfully generated and optimized ASOs that blunt the G(4)C(2) repeat-containing transcripts in the C9ORF72 gene, demonstrating potential therapeutic efficacy for patients with ALS and FTD.
Expansions of a G(4)C(2) 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 G(4)C(2) 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 G(4)C(2) 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据