Potent and sustained huntingtin lowering via AAV5 encoding miRNA preserves striatal volume and cognitive function in a humanized mouse model of Huntington disease
| العنوان: | Potent and sustained huntingtin lowering via AAV5 encoding miRNA preserves striatal volume and cognitive function in a humanized mouse model of Huntington disease |
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| المؤلفون: | Cynthia Brouwers, Pavlina Konstantinova, Amber L. Southwell, Hailey Findlay Black, Michael R. Hayden, Lisa M. Anderson, Nicholas S. Caron, Melvin M. Evers, Xiang Zhu, Seunghyun Ko, Louisa Dal Cengio, Yuanyun Xie, Sander J. H. van Deventer |
| المصدر: | Nucleic Acids Research |
| بيانات النشر: | Oxford University Press, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | congenital, hereditary, and neonatal diseases and abnormalities, Huntingtin, RNA Stability, Genetic Vectors, Gene Dosage, Context (language use), Biology, Pharmacology, Animals, Genetically Modified, 03 medical and health sciences, Mice, 0302 clinical medicine, Chemical Biology and Nucleic Acid Chemistry, Trinucleotide Repeats, Parvovirinae, microRNA, mental disorders, Genetics, medicine, Animals, Humans, Molecular Targeted Therapy, RNA, Messenger, 030304 developmental biology, Neurons, 0303 health sciences, Huntingtin Protein, Base Sequence, Wild type, Dependovirus, medicine.disease, Corpus Striatum, 3. Good health, Motor coordination, Astrogliosis, nervous system diseases, Disease Models, Animal, MicroRNAs, Huntington Disease, Tolerability, nervous system, Astrocytes, Humanized mouse, Neuroglia, 030217 neurology & neurosurgery, Psychomotor Performance |
| الوصف: | Huntington disease (HD) is a fatal neurodegenerative disease caused by a pathogenic expansion of a CAG repeat in the huntingtin (HTT) gene. There are no disease-modifying therapies for HD. Artificial microRNAs targeting HTT transcripts for degradation have shown preclinical promise and will soon enter human clinical trials. Here, we examine the tolerability and efficacy of non-selective HTT lowering with an AAV5 encoded miRNA targeting human HTT (AAV5-miHTT) in the humanized Hu128/21 mouse model of HD. We show that intrastriatal administration of AAV5-miHTT results in potent and sustained HTT suppression for at least 7 months post-injection. Importantly, non-selective suppression of huntingtin was generally tolerated, however high dose AAV5-miHTT did induce astrogliosis. We observed an improvement of select behavioural and modest neuropathological HD-like phenotypes in Hu128/21 mice, suggesting a potential therapeutic benefit of miRNA-mediated non-selective HTT lowering. Finally, we also observed that potent reduction of wild type HTT (wtHTT) in Hu21 control mice was tolerated up to 7 months post-injection but may induce impairment of motor coordination and striatal atrophy. Taken together, our data suggests that in the context of HD, the therapeutic benefits of mHTT reduction may outweigh the potentially detrimental effects of wtHTT loss following non-selective HTT lowering. |
| اللغة: | English |
| تدمد: | 1362-4962 0305-1048 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4726139682b402c98fa822b51aaaf5d5 http://europepmc.org/articles/PMC7145682 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....4726139682b402c98fa822b51aaaf5d5 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 13624962 03051048 |
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