Suppression of mutant C9orf72 expression by a potent mixed backbone antisense oligonucleotide
Authors
Tran, HeleneMoazami, Michael P.
Yang, Huiya
Mckenna-Yasek, Diane
Douthwright, Catherine
Pinto, Courtney
Metterville, Jake P.
Shin, Minwook
Sanil, Nitasha
Dooley, Craig
Puri, Ajit S.
Weiss, Alexandra
Wightman, Nicholas
Gray-Edwards, Heather L
Marosfoi, Miklos G.
King, Robert M.
Watts, Jonathan K.
Brown, Robert H. Jr.
UMass Chan Affiliations
Graduate School of Biomedical SciencesDepartment of Radiology
Research Pharmacy
RNA Therapeutics Institute
Department of Neurology
Document Type
Journal ArticlePublication Date
2021-12-23Keywords
Amyotrophic lateral sclerosisAntisense oligonucleotide therapy
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Medical Genetics
Molecular and Cellular Neuroscience
Nervous System Diseases
Nucleic Acids, Nucleotides, and Nucleosides
Therapeutics
UMCCTS funding
Metadata
Show full item recordAbstract
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.Source
Tran H, Moazami MP, Yang H, McKenna-Yasek D, Douthwright CL, Pinto C, Metterville J, Shin M, Sanil N, Dooley C, Puri A, Weiss A, Wightman N, Gray-Edwards H, Marosfoi M, King RM, Kenderdine T, Fabris D, Bowser R, Watts JK, Brown RH Jr. Suppression of mutant C9orf72 expression by a potent mixed backbone antisense oligonucleotide. Nat Med. 2021 Dec 23. doi: 10.1038/s41591-021-01557-6. Epub ahead of print. PMID: 34949835. Link to article on publisher's site
DOI
10.1038/s41591-021-01557-6Permanent Link to this Item
http://hdl.handle.net/20.500.14038/48577PubMed ID
34949835Notes
Full author list omitted for brevity. For the full list of authors, see article.
Related Resources
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10.1038/s41591-021-01557-6