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

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    Authors
    Tran, Helene
    Moazami, 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.
    Show allShow less
    UMass Chan Affiliations
    Graduate School of Biomedical Sciences
    Department of Radiology
    Research Pharmacy
    RNA Therapeutics Institute
    Department of Neurology
    Document Type
    Journal Article
    Publication Date
    2021-12-23
    Keywords
    Amyotrophic lateral sclerosis
    Antisense 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
    
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    Link to Full Text
    https://doi.org/10.1038/s41591-021-01557-6
    Abstract
    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/s41591-021-01557-6
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/48577
    PubMed ID
    34949835
    Notes

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

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    Link to Article in PubMed

    ae974a485f413a2113503eed53cd6c53
    10.1038/s41591-021-01557-6
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