Artificial miRNAs Reduce Human Mutant Huntingtin Throughout the Striatum in a Transgenic Sheep Model of Huntington's Disease

0499613 - ÚŽFG 2019 RIV US eng J - Článek v odborném periodiku
Pfister, E. L. - DiNardo, N. - Mondo, E. - Borel, F. - Conroy, F. - Fraser, C. - Gernoux, G. - Han, X. - Hu, D. - Johnson, E. - Kennington, L. - Liu, P. - Reid, S. J. - Sapp, E. - Vodička, Petr - Kuchel, T. - Morton, J. - Howland, D. S. - Moser, R. - Sena-Esteves, M. - Gao, G. - Mueller, C. - DiFiglia, M. - Aronin, N.
Artificial miRNAs Reduce Human Mutant Huntingtin Throughout the Striatum in a Transgenic Sheep Model of Huntington's Disease.
Human Gene Therapy. Roč. 29, č. 6 (2018), s. 663-673. ISSN 1043-0342. E-ISSN 1557-7422
Institucionální podpora: RVO:67985904
Klíčová slova: Huntington´s disease * large animal model * HTT
Obor OECD: Technologies involving the manipulation of cells, tissues, organs or the whole organism (assisted reproduction)
Impakt faktor: 3.855, rok: 2018

Huntington's disease (HD) is a fatal neurodegenerative disease caused by a genetic expansion of the CAG repeat region in the huntingtin (HTT) gene. Studies in HD mouse models have shown that artificial miRNAs can reduce mutant HTT, but evidence for their effectiveness and safety in larger animals is lacking. HD transgenic sheep express the full-length human HTT with 73 CAG repeats. AAV9 was used to deliver unilaterally to HD sheep striatum an artificial miRNA targeting exon 48 of the human HTT mRNA under control of two alternative promoters: U6 or CA. The treatment reduced human mutant (m) HTT mRNA and protein 50-80% in the striatum at 1 and 6 months post injection. Silencing was detectable in both the caudate and putamen. Levels of endogenous sheep HTT protein were not affected. There was no significant loss of neurons labeled by DARPP32 or NeuN at 6 months after treatment, and Iba1-positive microglia were detected at control levels. It is concluded that safe and effective silencing of human mHTT protein can be achieved and sustained in a large-animal brain by direct delivery of an AAV carrying an artificial miRNA.
Trvalý link: http://hdl.handle.net/11104/0291844