Počet záznamů: 1
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 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název AAV5-miHTT Gene Therapy Demonstrates Broad Distribution and Strong Human Mutant Huntingtin Lowering in a Huntington's Disease Minipig Model Tvůrce(i) 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)Zdroj.dok. Molecular Therapy. - : Cell Press - ISSN 1525-0016
Roč. 26, č. 9 (2018), s. 2163-2177Poč.str. 15 s. Forma vydání Tištěná - P Jazyk dok. eng - angličtina Země vyd. US - Spojené státy americké Klíč. slova Huntington´s disease ; minipig ; huntingtin Vědní obor RIV FH - Neurologie, neurochirurgie, neurovědy Obor OECD 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) CEP LO1609 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy Institucionální podpora UZFG-Y - RVO:67985904 UT WOS 000447756800010 EID SCOPUS 85049723970 DOI 10.1016/j.ymthe.2018.06.021 Anotace 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. Pracoviště Ústav živočišné fyziologie a genetiky Kontakt Jana Zásmětová, knihovna@iapg.cas.cz, Tel.: 315 639 554 Rok sběru 2019
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