I04 AAV5-MIHTT gene therapy demonstrates broad distribution and strong human mutant huntingtin lowering in a huntington disease minipig model
BackgroundHuntington disease (HD) is a fatal neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the huntingtin gene. Great effort has been put in proof-of-concept studies of therapeutic agents in HD rodent models. One of the challenges of rodents as a model of neurodegenera...
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Published in | Journal of neurology, neurosurgery and psychiatry Vol. 89; no. Suppl 1; p. A89 |
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Main Authors | , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
BMJ Publishing Group LTD
01.09.2018
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Abstract | BackgroundHuntington disease (HD) is a fatal neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the huntingtin gene. Great effort has been put in proof-of-concept studies of therapeutic agents in HD rodent models. 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 particular relevant for gene therapy approaches, where distribution achieved upon local administration into the parenchyma is likely dependent on brain size and structure.AimsHere, we investigated the feasibility, efficacy, and tolerability of huntingtin-lowering gene therapy in a large animal brain.MethodsTransgenic HD (tgHD) minipigs were injected with an engineered microRNA targeting human huntingtin, delivered via adeno-associated viral vector serotype 5 (AAV5-miHTT) or AAV5-GFP as control. The viruses were intracranially administered into the striatum and thalamus.ResultsWe 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.ConclusionThe 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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AbstractList | BackgroundHuntington disease (HD) is a fatal neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the huntingtin gene. Great effort has been put in proof-of-concept studies of therapeutic agents in HD rodent models. 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 particular relevant for gene therapy approaches, where distribution achieved upon local administration into the parenchyma is likely dependent on brain size and structure.AimsHere, we investigated the feasibility, efficacy, and tolerability of huntingtin-lowering gene therapy in a large animal brain.MethodsTransgenic HD (tgHD) minipigs were injected with an engineered microRNA targeting human huntingtin, delivered via adeno-associated viral vector serotype 5 (AAV5-miHTT) or AAV5-GFP as control. The viruses were intracranially administered into the striatum and thalamus.ResultsWe 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.ConclusionThe 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. |
Author | Petry, Harald Kovarova, Hana Klima, Jiri Vallès, Astrid van Deventer, Sander J Motlik, Jan Juhas, Stefan Konstantinova, Pavlina Vodicka, Petr Lubelski, Jacek Ellederova, Zdenka Miniarikova, Jana Juhasova, Jana Bohuslavova, Bozena Skalnikova, Helena Kupcova Brouwers, Cynthia Blits, Bas Evers, Melvin M Valekova, Ivona |
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Copyright | 2018 2018, Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions |
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Snippet | BackgroundHuntington disease (HD) is a fatal neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the huntingtin gene. Great effort has... |
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Title | I04 AAV5-MIHTT gene therapy demonstrates broad distribution and strong human mutant huntingtin lowering in a huntington disease minipig model |
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