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Cited by 174Amyotrophic Lateral Sclerosis ResearchRNA Interference and Gene DeliveryGenetic Neurodegenerative Diseases

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

Open access
Tran, Hélène, Moazami, Michael P., Yang, Huiya, McKenna-Yasek, Diane, Douthwright, Catherine L., Pinto, Courtney, Metterville, Jake, Shin, Minwook +13 more·2022·Nature Medicine
DOI 10.1038/s41591-021-01557-6PMC PMC8861976

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Abstract

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.

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  • Therapeutic trials of intrathecal antisense oligonucleotides designed to target expanded C9orf72 transcripts have only recruited people with an amyotrophic lateral sclerosis phenotype.

    “So far, therapeutic trials of intrathecal antisense oligonucleotides designed to target expanded C9orf72 transcripts (including BIIB078 and afinersen 86 ) have only recruited people with an amyotrophic lateral sclerosis phenotype.”

    From Advances and controversies in frontotemporal dementia: diagnosis, biomarkers, and therapeutic considerations (2022) · cites this paper as [86]

    The Results section (page unavailable) reports intrathecal afinersen treatment in one person with a C9ORF72 expansion and atypical motor neuron dysfunction. The paper supports that example, but it does not establish that all such trials—including BIIB078—recruited only people with an ALS phenotype. (LLM, conf=0.84)

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References 64 · Cited by 174

Research works printed but not linked: 38

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Authors
Tran, H., Moazami, M. P., Yang, H., McKenna-Yasek, D., Douthwright, C. L., Pinto, C., Metterville, J., Shin, M., Sanil, N., Dooley, C., Puri, A., Weiss, A., Wightman, N., Gray-Edwards, H., Marosfoi, M., King, R. M., Kenderdine, T., Fabris, D., Bowser, R., Watts, J. K., & Brown, R. H.
Affiliations
  • University of Massachusetts Chan Medical School (US)
  • Worcester Polytechnic Institute (US)
  • University of Connecticut (US)
  • Barrow Neurological Institute (US)
Corresponding author
  • Watts, Jonathan K.
  • Brown, Robert H.
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2021-12-23
Volume
28
Issue
1
Pages
117-124
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/s41591-021-01557-6
PMC
PMC8861976
OpenAlex
W4200583678
Cited by
174
References
64
Citations by year
2026: 21 · 2025: 40 · 2024: 48 · 2023: 38 · 2022: 26 · 2021: 1
FWCI
13.52
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Medicine (publishedVersion)
  • Research Square (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship@UMassChan (submittedVersion)
Funders
  • U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (RO1 NS111990)
  • Angel Fund for ALS Research ALS-One ALSFindingACure Cellucci Fund Max Rosenfeld Fund for ALS Research Target ALS
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
Keywords
C9orf72, G4C2 repeat expansion, antisense oligonucleotides, amyotrophic lateral sclerosis, frontotemporal dementia, phosphorothioate, intrathecal drug delivery, cerebrospinal fluid, gene silencing, patient-derived cells, BAC transgenic mice
MeSH terms
C9orf72 Protein, Animals, Fibroblasts, Humans, Mice, Transgenic, Mutation, Neurons, Oligonucleotides, Antisense, Mice

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