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AAV5-miHTT Gene Therapy Demonstrates Broad Distribution and Strong Human Mutant Huntingtin Lowering in a Huntington's Disease Minipig Model
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SYSNO ASEP 0496209 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title AAV5-miHTT Gene Therapy Demonstrates Broad Distribution and Strong Human Mutant Huntingtin Lowering in a Huntington's Disease Minipig Model Author(s) Evers, M. (NL)
Miniarikova, J. (NL)
Juhás, Štefan (UZFG-Y) RID, ORCID
Vallés, A. (NL)
Bohuslavová, Božena (UZFG-Y) ORCID
Juhásová, Jana (UZFG-Y) RID, ORCID
Kupcová Skalníková, Helena (UZFG-Y) RID, ORCID
Vodička, Petr (UZFG-Y) ORCID
Valeková, Ivona (UZFG-Y) RID, ORCID
Brouwers, C. (NL)
Blits, B. (NL)
Lubelski, J. (NL)
Kovářová, Hana (UZFG-Y) RID, ORCID
Ellederová, Zdeňka (UZFG-Y) RID, ORCID
van Deventer, S. (NL)
Petry, H. (NL)
Motlík, Jan (UZFG-Y) RID, ORCID
Konstantinová, P. (NL)Source Title Molecular Therapy. - : Cell Press - ISSN 1525-0016
Roč. 26, č. 9 (2018), s. 2163-2177Number of pages 15 s. Publication form Print - P Language eng - English Country US - United States Keywords Huntington´s disease ; minipig ; huntingtin Subject RIV FH - Neurology OECD category Technologies involving identifying the functioning of DNA, proteins and enzymes and how they influence the onset of disease and maintenance of well-being (gene-based diagnostics and therapeutic interventions (pharmacogenomics, gene-based therapeutics) R&D Projects LO1609 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Institutional support UZFG-Y - RVO:67985904 UT WOS 000447756800010 EID SCOPUS 85049723970 DOI https://doi.org/10.1016/j.ymthe.2018.06.021 Annotation Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the huntingtin gene. Previously, we showed strong huntingtin reduction and prevention of neuronal dysfunction in HD rodents using an engineered microRNA targeting human huntingtin, delivered via adeno-associated virus (AAV) serotype 5 vector with a transgene encoding an engineered miRNA against HTT mRNA (AAV5-miHTT). One of the challenges of rodents as a model of neurodegenerative diseases is their relatively small brain, making successful translation to the HD patient difficult. This is particularly relevant for gene therapy approaches, where distribution achieved upon local administration into the parenchyma is likely dependent on brain size and structure. Here, we aimed to demonstrate the translation of huntingtin-lowering gene therapy to a large-animal brain. We investigated the feasibility, efficacy, and tolerability of one-time intracranial administration of AAV5-miHTT in the transgenic HD(tgHD) minipig model. We detected widespread dose-dependent distribution of AAV5-miHTT throughout the tgHD minipig brain that correlated with the engineered microRNA expression. Both human mutant huntingtin mRNA and protein were significantly reduced in all brain regions transduced by AAV5-miHTT. The combination of widespread vector distribution and extensive huntingtin lowering observed with AAV5-miHTT supports the translation of a huntingtin-lowering gene therapy for HD from preclinical studies into the clinic. Workplace Institute of Animal Physiology and Genetics Contact Jana Zásmětová, knihovna@iapg.cas.cz, Tel.: 315 639 554 Year of Publishing 2019
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