Exon 1-targeting miRNA reduces the pathogenic exon 1 HTT protein in Huntington's disease models
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Le résumé fourni par la source
Huntington's disease (HD) is a fatal neurodegenerative disease caused by a trinucleotide repeat expansion in exon 1 of the huntingtin gene (HTT) that results in toxic gain of function and cell death. Despite its monogenic cause, the pathogenesis of HD is highly complex, and increasing evidence indicates that, in addition to the full-length (FL) mutant HTT protein, the expanded exon 1 HTT (HTTexon1) protein that is translated from the HTT1a transcript generated by aberrant splicing is prone to aggregate and might contribute to HD pathology. This finding suggests that reducing the expression of HTT1a might achieve a greater therapeutic benefit than targeting only FL mutant HTT. Conversely, strategies that exclusively target FL HTT might not completely prevent the pathogenesis of HD. We have developed an engineered microRNA targeting the HTT exon 1 sequence (miHTT), delivered via adeno-associated virus serotype 5 (AAV5). The target sequence of miHTT is present in both FL HTT and HTT1a transcripts. Preclinical studies with AAV5-miHTT have demonstrated efficacy in several rodent and large animal models by reducing FL HTT mRNA and protein and rescuing HD-like phenotypes and have been the rationale for phase I/II clinical studies now ongoing in the USA and Europe. In the present study, we evaluated the ability of AAV5-miHTT to reduce the levels of aberrantly spliced HTT1a mRNA and the HTTexon1 protein in the brain of two mouse models of HD (heterozygous zQ175 knock-in mice and humanized Hu128/21 mice). Polyadenylated HTT1a mRNA and HTTexon1 protein were detected in the striatum and cortex of heterozygous zQ175 knock-in mice, but not in wild-type littermate control mice. Intrastriatal administration of AAV5-miHTT resulted in dose-dependent expression of mature miHTT microRNA in cortical brain regions, accompanied by significant lowering of both FL HTT and HTT1a mRNA expression at 2 months postinjection. Mutant HTT and HTTexon1 protein levels were also significantly reduced in the striatum and cortex of heterozygous zQ175 knock-in mice at 2 months after AAV5-miHTT treatment and in humanized Hu128/21 mice 7 months post-treatment. The effects were confirmed in primary Hu128/21 neuronal cultures. These results demonstrate that AAV5-miHTT gene therapy is an effective approach to lower both FL HTT and the pathogenic HTTexon1 levels, which could potentially have an additive therapeutic benefit in comparison to other HTT-targeting modalities.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Exon 1-targeting miRNA reduces the pathogenic exon 1 HTT protein in Huntington's disease models
- Date Crossref
- 18/08/2024
- Éditeur
- Oxford University Press (OUP)
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Leiden University Medical Center Department of Gastroenterology and Hepatology pays non établi dans la noticeOrganisme public
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UniQure (Netherlands) pays non établi dans la noticeEntreprise
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UK Dementia Research Institute Huntington’s Disease Centre pays non établi dans la noticeStructure de recherche
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National Hospital for Neurology and Neurosurgery pays non établi dans la noticeÉtablissement de santé
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UCL Queen Square Institute of Neurology pays non établi dans la noticeUniversité ou école supérieure
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University College London pays non établi dans la noticeUniversité ou école supérieure
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University of British Columbia Department of Medical Genetics pays non établi dans la noticeUniversité ou école supérieure
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CHDI Foundation pays non établi dans la noticeOrganisation à but non lucratif
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Department of Research & Development pays non établi dans la noticeInstitution
Department of Gastroenterology and Hepatology — Leiden University Medical Center, UniQure (Netherlands) et Huntington’s Disease Centre — UK Dementia Research Institute, avec 6 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.