Single nucleotide seed modification restores in vivo tolerability of a toxic artificial miRNA sequence in the mouse brain

Alex M as Monteys, Ryan M. Spengler, Brett D. Dufour, Matt S. Wilson, Clayton K. Oakley, Matt J. Sowada, Jodi McBride, Beverly L. Davidson

    Research output: Contribution to journalArticle

    12 Citations (Scopus)

    Abstract

    Huntington's disease is a fatal neurodegenerative disease caused by polyglutamine-expansion in huntingtin (HTT). Recent work showed that gene silencing approaches, including RNA interference (RNAi), improve disease readouts in mice. To advance RNAi to the clinic, we designed miHDS1, with robust knockdown of human HTT and minimized silencing of unintended transcripts. In Rhesus macaque, AAV delivery of miHDS1 to the putamen reduced HTT expression with no adverse effects on neurological status including fine and gross motor skills, no immune activation and no induction of neuropathology out to 6 weeks post injection. Others showed safety of a different HTT-targeting RNAi in monkeys for 6 months. Application of miHDS1 to Huntington's patients requires further safety testing in normal rodents, despite the fact that it was optimized for humans. To satisfy this regulatory requirement, we evaluated normal mice after AAV.miHDS1 injection. In contrast to monkeys, neurological deficits occurred acutely in mice brain and was attributed to off-target silencing through interactions of miHDS1 with the 3'UTR of other transcripts. While we resolved miHDS1 toxicity in mouse brain and maintained miHDS1-silencing efficacy, these studies highlight that optimizing nucleic acid-based medicines for safety in humans presents challenges for safety testing in rodents or other distantly related species.

    Original languageEnglish (US)
    Pages (from-to)13315-13327
    Number of pages13
    JournalNucleic Acids Research
    Volume42
    Issue number21
    DOIs
    StatePublished - Dec 1 2014

    Fingerprint

    Poisons
    MicroRNAs
    Seeds
    Nucleotides
    RNA Interference
    Safety
    Brain
    Haplorhini
    Rodentia
    Injections
    Motor Skills
    Putamen
    Huntington Disease
    3' Untranslated Regions
    Gene Silencing
    Macaca mulatta
    Neurodegenerative Diseases
    Nucleic Acids

    ASJC Scopus subject areas

    • Medicine(all)

    Cite this

    Monteys, A. M. A., Spengler, R. M., Dufour, B. D., Wilson, M. S., Oakley, C. K., Sowada, M. J., ... Davidson, B. L. (2014). Single nucleotide seed modification restores in vivo tolerability of a toxic artificial miRNA sequence in the mouse brain. Nucleic Acids Research, 42(21), 13315-13327. https://doi.org/10.1093/nar/gku979

    Single nucleotide seed modification restores in vivo tolerability of a toxic artificial miRNA sequence in the mouse brain. / Monteys, Alex M as; Spengler, Ryan M.; Dufour, Brett D.; Wilson, Matt S.; Oakley, Clayton K.; Sowada, Matt J.; McBride, Jodi; Davidson, Beverly L.

    In: Nucleic Acids Research, Vol. 42, No. 21, 01.12.2014, p. 13315-13327.

    Research output: Contribution to journalArticle

    Monteys, AMA, Spengler, RM, Dufour, BD, Wilson, MS, Oakley, CK, Sowada, MJ, McBride, J & Davidson, BL 2014, 'Single nucleotide seed modification restores in vivo tolerability of a toxic artificial miRNA sequence in the mouse brain', Nucleic Acids Research, vol. 42, no. 21, pp. 13315-13327. https://doi.org/10.1093/nar/gku979
    Monteys, Alex M as ; Spengler, Ryan M. ; Dufour, Brett D. ; Wilson, Matt S. ; Oakley, Clayton K. ; Sowada, Matt J. ; McBride, Jodi ; Davidson, Beverly L. / Single nucleotide seed modification restores in vivo tolerability of a toxic artificial miRNA sequence in the mouse brain. In: Nucleic Acids Research. 2014 ; Vol. 42, No. 21. pp. 13315-13327.
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