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

Hélène Tran, Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
Michael P. Moazami, RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA.
Huiya Yang, Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
Diane McKenna-Yasek, Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
Catherine L. Douthwright, Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
Courtney Pinto, Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
Jake Metterville, Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
Minwook Shin, RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA.
Nitasha Sanil, Research Pharmacy, University of Massachusetts Medical School, Worcester, MA, USA.
Craig Dooley, Research Pharmacy, University of Massachusetts Medical School, Worcester, MA, USA.
Ajit Puri, Department of Radiology, University of Massachusetts Medical School, Worcester, MA, USA.
Alexandra Weiss, Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
Nicholas Wightman, Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
Heather Gray-Edwards, Department of Radiology, University of Massachusetts Medical School, Worcester, MA, USA.
Miklos Marosfoi, Department of Radiology, University of Massachusetts Medical School, Worcester, MA, USA.
Robert M. King, Department of Radiology, University of Massachusetts Medical School, Worcester, MA, USA.
Thomas Kenderdine, Department of Chemistry, University of Connecticut, Storrs, CT, USA.
Daniele Fabris, Department of Chemistry, University of Connecticut, Storrs, CT, USA.
Robert Bowser, Departments of Neurology and Neurobiology, Barrow Neurological Institute, Phoenix, AZ, USA.Follow
Jonathan K. Watts, RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA. jonathan.watts@umassmed.edu.
Robert H. Brown, Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA. robert.brown@umassmed.edu.

Document Type

Article

Abstract

Expansions of a GC 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 GC 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 GC 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.

Medical Subject Headings

Animals; C9orf72 Protein (genetics, metabolism); Fibroblasts (metabolism); Humans; Mice; Mice, Transgenic; Mutation; Neurons (metabolism); Oligonucleotides, Antisense (genetics)

Publication Date

1-1-2022

Publication Title

Nature medicine

E-ISSN

1546-170X

Volume

28

Issue

1

First Page

117

Last Page

124

PubMed ID

34949835

Digital Object Identifier (DOI)

10.1038/s41591-021-01557-6

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