AAV5-miHTT Gene Therapy Demonstrates Broad Distribution and Strong Human Mutant Huntingtin Lowering in a Huntington’s Disease Minipig Model

• Published in: Molecular therapy Vol. 26; no. 9; pp. 2163 - 2177
• Main Authors: Evers, Melvin M., Miniarikova, Jana, Juhas, Stefan, Vallès, Astrid, Bohuslavova, Bozena, Juhasova, Jana, Skalnikova, Helena Kupcova, Vodicka, Petr, Valekova, Ivona, Brouwers, Cynthia, Blits, Bas, Lubelski, Jacek, Kovarova, Hana, Ellederova, Zdenka, van Deventer, Sander J., Petry, Harald, Motlik, Jan, Konstantinova, Pavlina
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.09.2018; Elsevier Limited; American Society of Gene & Cell Therapy
• Subjects: AAV; Animal models; Disease; gene silencing; Gene therapy; Huntingtin; Huntington disease; Huntington's disease; Huntingtons disease; microRNA; miRNA; mRNA; Neurodegeneration; Neurodegenerative diseases; Original; Parenchyma; Polyglutamine; Proteins; Spinal cord; Statistical analysis; transgenic minipig; Translation; Trinucleotide repeats; gene silencing; microRNA; transgenic minipig; AAV; Huntington disease
• ISSN: 1525-0016; 1525-0024; 1525-0024
• DOI: 10.1016/j.ymthe.2018.06.021

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. AAV5-miHTT gene therapy demonstrates broad distribution and strong human mutant huntingtin lowering in the brain of a Huntington’s disease minipig model. Evers and colleagues show that one-time intracranial administration of a microRNA-based gene therapy was feasible, well tolerated, and resulted in dose-dependent reduction of toxic human huntingtin protein in the transgenic minipig model of Huntington’s disease. This is the first demonstration of widespread human mutant huntingtin lowering in the large-animal model.