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A CAG repeat-targeting artificial miRNA lowers the mutant huntingtin level in the YAC128 model of Huntington's disease

dc.abstract.enAmong the many proposed therapeutic strategies for Huntington’s disease (HD), allele-selective therapies are the most desirable but also the most challenging. RNA interference (RNAi) tools that target CAG repeats selectively reduce the mutant huntingtin level in cellular models of HD. The purpose of this study was to test the efficacy, selectivity, and safety of two vector-based RNAi triggers in an animal model of HD. CAG repeat-targeting short hairpin RNA (shRNA) and artificial miRNA (amiRNA) were delivered to the brains of YAC128 mice via intrastriatal injection of AAV5 vectors. Molecular tests demonstrated that both the shRNA and amiRNA reduced the mutant huntingtin level by 50% without influencing endogenous mouse huntingtin. In addition, a concentration-dependent reduction in HTT aggregates in the striatum was observed. In contrast to the shRNA, the amiRNA was well tolerated and did not show signs of toxicity during the course of the experiment up to 20 weeks post injection. Interestingly, amiRNA treatment reduced the spleen weight to values characteristic of healthy (WT) mice and improved motor performance on the static rod test. These preclinical data demonstrate that the CAG-targeting strategy and amiRNA could make an original and valuable contribution to currently used therapeutic approaches for HD.
dc.affiliationWydział Rolnictwa, Ogrodnictwa i Bioinżynierii
dc.affiliation.instituteKatedra Biochemii i Biotechnologii
dc.contributor.authorKotowska-Zimmer, Anna
dc.contributor.authorPrzybyl, Lukasz
dc.contributor.authorPewinska, Marianna
dc.contributor.authorSuszyńska-Zajczyk, Joanna
dc.contributor.authorWronka, Dorota
dc.contributor.authorFigiel, Maciej
dc.contributor.authorOlejniczak, Marta
dc.date.access2026-03-20
dc.date.accessioned2026-03-20T10:37:26Z
dc.date.available2026-03-20T10:37:26Z
dc.date.copyright2022-05-05
dc.date.issued2022
dc.description.accesstimeat_publication
dc.description.bibliographyil., bibliogr.
dc.description.financepublication_nocost
dc.description.financecost0,00
dc.description.if8,8
dc.description.number14 June 2022
dc.description.points140
dc.description.versionfinal_published
dc.description.volume28
dc.identifier.doi10.1016/j.omtn.2022.04.031
dc.identifier.issn2162-2531
dc.identifier.urihttps://sciencerep.up.poznan.pl/handle/item/7835
dc.identifier.weblinkhttps://www.sciencedirect.com/science/article/pii/S2162253122001081
dc.languageen
dc.relation.ispartofMolecular Therapy - Nucleic Acids
dc.relation.pages702-715
dc.rightsCC-BY
dc.sciencecloudnosend
dc.share.typeOPEN_JOURNAL
dc.titleA CAG repeat-targeting artificial miRNA lowers the mutant huntingtin level in the YAC128 model of Huntington's disease
dc.typeJournalArticle
dspace.entity.typePublication
oaire.citation.volume28