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

UMMS Affiliation

Department of Neurology; RNA Therapeutics Institute; Research Pharmacy; Department of Radiology; Graduate School of Biomedical Sciences

Publication Date


Document Type



Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Medical Genetics | Molecular and Cellular Neuroscience | Nervous System Diseases | Nucleic Acids, Nucleotides, and Nucleosides | Therapeutics


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.


Amyotrophic lateral sclerosis, Antisense oligonucleotide therapy

DOI of Published Version



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

Journal/Book/Conference Title

Nature medicine


Full author list omitted for brevity. For the full list of authors, see article.

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