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

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985904%3A_____%2F18%3A00496209" target="_blank" >RIV/67985904:_____/18:00496209 - isvavai.cz</a>

Result on the web

<a href="http://dx.doi.org/10.1016/j.ymthe.2018.06.021" target="_blank" >http://dx.doi.org/10.1016/j.ymthe.2018.06.021</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.ymthe.2018.06.021" target="_blank" >10.1016/j.ymthe.2018.06.021</a>

Result language

angličtina

Original language name

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

Original language description

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.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30103 - Neurosciences (including psychophysiology)

Project

<a href="/en/project/LO1609" target="_blank" >LO1609: Models of the Serious Human Diseases: Traumatic Spinal Cord Injury, Huntington’s Disease, Melanoma and Infertility</a><br>

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2018

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Molecular Therapy

ISSN

1525-0016

e-ISSN

—

Volume of the periodical

26

Issue of the periodical within the volume

9

Country of publishing house

US - UNITED STATES

Number of pages

15

Pages from-to

2163-2177

UT code for WoS article

000447756800010

EID of the result in the Scopus database

2-s2.0-85049723970