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

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

    Research output: Contribution to journalArticle

    13 Scopus citations

    Abstract

    Huntington's disease is a fatal neurodegenerative disease caused by polyglutamine-expansion in huntingtin (HTT). Recentwork 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 - Jan 1 2014

    ASJC Scopus subject areas

    • Genetics

    Fingerprint Dive into the research topics of 'Single nucleotide seed modification restores in vivo tolerability of a toxic artificial miRNA sequence in the mouse brain'. Together they form a unique fingerprint.

  • Cite this

    Monteys, A. M., Spengler, R. M., Dufour, B. D., Wilson, M. S., Oakley, C. K., Sowada, M. J., McBride, J. L., & 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