Suppression of mutant C9orf72 expression by a potent mixed backbone antisense oligonucleotide.

Autor: Tran H; Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA., Moazami MP; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA., Yang H; Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA., McKenna-Yasek D; Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA., Douthwright CL; Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA., Pinto C; Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA., Metterville J; Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA., Shin M; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA., Sanil N; Research Pharmacy, University of Massachusetts Medical School, Worcester, MA, USA., Dooley C; Research Pharmacy, University of Massachusetts Medical School, Worcester, MA, USA., Puri A; Department of Radiology, University of Massachusetts Medical School, Worcester, MA, USA., Weiss A; Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA., Wightman N; Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA., Gray-Edwards H; Department of Radiology, University of Massachusetts Medical School, Worcester, MA, USA., Marosfoi M; Department of Radiology, University of Massachusetts Medical School, Worcester, MA, USA., King RM; Department of Radiology, University of Massachusetts Medical School, Worcester, MA, USA.; Department of Biomedical Engineering, Worcester Polytechnic Institute, Worcester, MA, USA., Kenderdine T; Department of Chemistry, University of Connecticut, Storrs, CT, USA., Fabris D; Department of Chemistry, University of Connecticut, Storrs, CT, USA., Bowser R; Departments of Neurology and Neurobiology, Barrow Neurological Institute, Phoenix, AZ, USA., Watts JK; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA. jonathan.watts@umassmed.edu., Brown RH Jr; Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA. robert.brown@umassmed.edu.
Jazyk: angličtina
Zdroj: Nature medicine [Nat Med] 2022 Jan; Vol. 28 (1), pp. 117-124. Date of Electronic Publication: 2021 Dec 23.
DOI: 10.1038/s41591-021-01557-6
Abstrakt: 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.
(© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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