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Cited by 168Virus-based gene therapy researchGenetic Neurodegenerative DiseasesRNA Interference and Gene Delivery

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

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Evers, Melvin M., Miniarikova, Jana, Juhas, Stefan, Vallès, Astrid, Bohuslavova, Bozena, Juhasova, Jana, Skalnikova, Helena Kupcova, Vodicka, Petr +10 more·2018·Molecular Therapy
DOI 10.1016/j.ymthe.2018.06.021PMC PMC6127509
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Abstract

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.

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  • Multiple injections of AAV are required due to the limited distribution achieved with a single injection.

    “However, multiple injections of AAV are required due to the limited distribution achieved with a single injection.”

    From A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system (2019) · cites this paper as [41]

    The Results section reports transduction in the thalamus, striatum and cortex after thalamic injection, and the Discussion describes favorable widespread brain distribution after thalamic injection. Although the paper finds that intrathecal injection reaches deep brain structures poorly and favors combined striatal and thalamic delivery for Huntington’s disease, it does not say that AAV generally requires multiple injections because a single injection has limited distribution. Page numbers are unavailable in our copy. (LLM, conf=0.84)

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  • AAV delivered by intra-parenchymal injections efficiently silenced HTT in minipig, sheep, and NHP.

    “AAV delivered by intra-parenchymal injections efficiently silenced HTT in minipig, sheep, and NHP 41, 43, 44.”

    From A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system (2019) · cites this paper as [41]

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Authors
Evers, M. M., Miniarikova, J., Juhas, S., Vallès, A., Bohuslavova, B., Juhasova, J., Skalnikova, H. K., Vodicka, P., Valekova, I., Brouwers, C., Blits, B., Lubelski, J., Kovarova, H., Ellederova, Z., van Deventer, S. J., Petry, H., Motlik, J., & Konstantinova, P.
Affiliations
UniQure (Netherlands) (NL)
Corresponding author
Evers, Melvin M.
ORCID
Venue
Molecular Therapy
Publisher
Elsevier BV
Published
2018-09
Volume
26
Issue
9
Pages
2163-2177
ISSN
1525-0016 (ISSN-L)
DOI
10.1016/j.ymthe.2018.06.021
PMC
PMC6127509
OpenAlex
W2811325414
Cited by
168
References
72
Citations by year
2026: 15 · 2025: 9 · 2024: 26 · 2023: 13 · 2022: 26 · 2021: 32 · 2020: 25 · 2019: 21 · 2018: 1
FWCI
12.09
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Therapy (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • CHDI Foundation
  • Ministerstvo Školství, Mládeže a Tělovýchovy
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Keywords
Huntington's disease, gene therapy, vector distribution, intracranial administration, large animal model, CAG repeat expansion, transgene expression
MeSH terms
Huntingtin Protein, Dependovirus, Animals, Disease Models, Animal, Genetic Vectors, Humans, Huntington Disease, Swine, Swine, Miniature, Genetic Therapy, Trinucleotide Repeat Expansion, Animals, Genetically Modified, MicroRNAs

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