{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T04:21:04Z","timestamp":1791865264596,"version":"4.3.4"},"reference-count":76,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2019,11,20]],"date-time":"2019-11-20T00:00:00Z","timestamp":1574208000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ripples of Hope Pfizer Trainee Award"},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"name":"James Family Fellowship"},{"DOI":"10.13039\/100000887","name":"Huntington's Disease Society of America","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000887","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000245","name":"Michael Smith Foundation for Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000245","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>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.<\/jats:p>","DOI":"10.1093\/nar\/gkz976","type":"journal-article","created":{"date-parts":[[2019,10,16]],"date-time":"2019-10-16T22:19:30Z","timestamp":1571264370000},"source":"Crossref","is-referenced-by-count":20,"title":["Potent and sustained huntingtin lowering via AAV5 encoding miRNA preserves striatal volume and cognitive function in a humanized mouse model of Huntington disease"],"prefix":"10.1093","author":[{"given":"Nicholas S","family":"Caron","sequence":"first","affiliation":[{"name":"Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada"},{"name":"Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada"},{"name":"BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amber L","family":"Southwell","sequence":"additional","affiliation":[{"name":"Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada"},{"name":"Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada"},{"name":"BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada"},{"name":"Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia C","family":"Brouwers","sequence":"additional","affiliation":[{"name":"Department of Research & Development, uniQure biopharma B.V., Amsterdam, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louisa Dal","family":"Cengio","sequence":"additional","affiliation":[{"name":"Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyun","family":"Xie","sequence":"additional","affiliation":[{"name":"Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada"},{"name":"Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hailey Findlay","family":"Black","sequence":"additional","affiliation":[{"name":"Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada"},{"name":"Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada"},{"name":"BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa M","family":"Anderson","sequence":"additional","affiliation":[{"name":"Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seunghyun","family":"Ko","sequence":"additional","affiliation":[{"name":"Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Zhu","sequence":"additional","affiliation":[{"name":"Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sander J","family":"van\u00a0Deventer","sequence":"additional","affiliation":[{"name":"Department of Research & Development, uniQure biopharma B.V., Amsterdam, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melvin M","family":"Evers","sequence":"additional","affiliation":[{"name":"Department of Research & Development, uniQure biopharma B.V., Amsterdam, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavlina","family":"Konstantinova","sequence":"additional","affiliation":[{"name":"Department of Research & Development, uniQure biopharma B.V., Amsterdam, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R","family":"Hayden","sequence":"additional","affiliation":[{"name":"Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada"},{"name":"Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada"},{"name":"BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,11,20]]},"reference":[{"key":"2019112003002055700_B1","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1002\/mds.25717","article-title":"Multisource ascertainment of Huntington disease in Canada: prevalence and population at risk","volume":"29","author":"Fisher","year":"2014","journal-title":"Mov. Disord."},{"key":"2019112003002055700_B2","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1016\/0092-8674(93)90585-E","article-title":"A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group","volume":"72","year":"1993","journal-title":"Cell"},{"key":"2019112003002055700_B3","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1126\/science.1059581","article-title":"Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease","volume":"293","author":"Zuccato","year":"2001","journal-title":"Science"},{"key":"2019112003002055700_B4","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1038\/ng1219","article-title":"Huntingtin interacts with REST\/NRSF to modulate the transcription of NRSE-controlled neuronal genes","volume":"35","author":"Zuccato","year":"2003","journal-title":"Nat. Genet."},{"key":"2019112003002055700_B5","doi-asserted-by":"crossref","first-page":"7466","DOI":"10.1074\/jbc.M103946200","article-title":"Huntingtin is present in the nucleus, interacts with the transcriptional corepressor C-terminal binding protein, and represses transcription","volume":"277","author":"Kegel","year":"2002","journal-title":"J. Biol. Chem."},{"key":"2019112003002055700_B6","doi-asserted-by":"crossref","first-page":"30773","DOI":"10.1074\/jbc.M504749200","article-title":"Mitochondrial respiration and ATP production are significantly impaired in striatal cells expressing mutant huntingtin","volume":"280","author":"Milakovic","year":"2005","journal-title":"J. Biol. Chem."},{"key":"2019112003002055700_B7","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1038\/nn884","article-title":"Early mitochondrial calcium defects in Huntington's disease are a direct effect of polyglutamines","volume":"5","author":"Panov","year":"2002","journal-title":"Nat. Neurosci."},{"key":"2019112003002055700_B8","doi-asserted-by":"crossref","first-page":"8195","DOI":"10.1128\/MCB.24.18.8195-8209.2004","article-title":"Mutant huntingtin impairs axonal trafficking in mammalian neurons in vivo and in vitro","volume":"24","author":"Trushina","year":"2004","journal-title":"Mol. Cell Biol."},{"key":"2019112003002055700_B9","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/S0896-6273(03)00594-4","article-title":"Disruption of axonal transport by loss of huntingtin or expression of pathogenic polyQ proteins in Drosophila","volume":"40","author":"Gunawardena","year":"2003","journal-title":"Neuron"},{"key":"2019112003002055700_B10","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.cell.2004.06.018","article-title":"Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules","volume":"118","author":"Gauthier","year":"2004","journal-title":"Cell"},{"key":"2019112003002055700_B11","doi-asserted-by":"crossref","first-page":"3578","DOI":"10.1093\/hmg\/ddl434","article-title":"Mutant huntingtin inhibits clathrin-independent endocytosis and causes accumulation of cholesterol in vitro and in vivo","volume":"15","author":"Trushina","year":"2006","journal-title":"Hum. Mol. Genet."},{"key":"2019112003002055700_B12","doi-asserted-by":"crossref","first-page":"6106","DOI":"10.1128\/MCB.00420-09","article-title":"Mutant huntingtin impairs vesicle formation from recycling endosomes by interfering with Rab11 activity","volume":"29","author":"Li","year":"2009","journal-title":"Mol. Cell Biol."},{"key":"2019112003002055700_B13","doi-asserted-by":"crossref","first-page":"2600","DOI":"10.1093\/hmg\/ddm217","article-title":"Huntingtin has a membrane association signal that can modulate huntingtin aggregation, nuclear entry and toxicity","volume":"16","author":"Atwal","year":"2007","journal-title":"Hum. Mol. Genet."},{"key":"2019112003002055700_B14","doi-asserted-by":"crossref","first-page":"1937","DOI":"10.1093\/hmg\/ddr075","article-title":"Mutant huntingtin causes defective actin remodeling during stress: defining a new role for transglutaminase 2 in neurodegenerative disease","volume":"20","author":"Munsie","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"2019112003002055700_B15","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1093\/hmg\/ddu460","article-title":"A huntingtin-mediated fast stress response halting endosomal trafficking is defective in Huntington's disease","volume":"24","author":"Nath","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"2019112003002055700_B16","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/S0092-8674(00)80623-6","article-title":"Reversal of neuropathology and motor dysfunction in a conditional model of Huntington's disease","volume":"101","author":"Yamamoto","year":"2000","journal-title":"Cell"},{"key":"2019112003002055700_B17","doi-asserted-by":"crossref","first-page":"5820","DOI":"10.1073\/pnas.0501507102","article-title":"RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model","volume":"102","author":"Harper","year":"2005","journal-title":"PNAS"},{"key":"2019112003002055700_B18","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1038\/mt.2008.50","article-title":"AAV vector-mediated RNAi of mutant huntingtin expression is neuroprotective in a novel genetic rat model of Huntington's disease","volume":"16","author":"Franich","year":"2008","journal-title":"Mol. 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Ther."},{"key":"2019112003002055700_B21","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.bbrc.2006.02.141","article-title":"rAAV-mediated shRNA ameliorated neuropathology in Huntington disease model mouse","volume":"343","author":"Machida","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2019112003002055700_B22","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.neures.2005.06.021","article-title":"Clinico-pathological rescue of a model mouse of Huntington's disease by siRNA","volume":"53","author":"Wang","year":"2005","journal-title":"Neurosci. 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Gene Ther."},{"key":"2019112003002055700_B25","doi-asserted-by":"crossref","first-page":"217","DOI":"10.3233\/JHD-130057","article-title":"Antisense oligonucleotide-mediated correction of transcriptional dysregulation is correlated with behavioral benefits in the YAC128 mouse model of Huntington's disease","volume":"2","author":"Stanek","year":"2013","journal-title":"J. Huntington's Dis."},{"key":"2019112003002055700_B26","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1002\/ana.21569","article-title":"Sustained effects of nonallele-specific Huntingtin silencing","volume":"65","author":"Drouet","year":"2009","journal-title":"Ann. 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Ther."},{"key":"2019112003002055700_B30","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1016\/j.molmed.2012.09.001","article-title":"Antisense oligonucleotide therapeutics for inherited neurodegenerative diseases","volume":"18","author":"Southwell","year":"2012","journal-title":"Trends Mol. Med."},{"key":"2019112003002055700_B31","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1038\/nrd.2018.133","article-title":"Therapeutic approaches to Huntington disease: from the bench to the clinic","volume":"17","author":"Caron","year":"2018","journal-title":"Nat. Rev. Drug Discov."},{"key":"2019112003002055700_B32","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1038\/35888","article-title":"Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans","volume":"391","author":"Fire","year":"1998","journal-title":"Nature"},{"key":"2019112003002055700_B33","doi-asserted-by":"crossref","first-page":"17204","DOI":"10.1073\/pnas.0708285104","article-title":"Therapeutic silencing of mutant huntingtin with siRNA attenuates striatal and cortical neuropathology and behavioral deficits","volume":"104","author":"DiFiglia","year":"2007","journal-title":"PNAS"},{"key":"2019112003002055700_B34","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1016\/j.chembiol.2010.10.013","article-title":"Allele-selective inhibition of huntingtin expression by switching to an miRNA-like RNAi mechanism","volume":"17","author":"Hu","year":"2010","journal-title":"Chem. Biol."},{"key":"2019112003002055700_B35","doi-asserted-by":"crossref","first-page":"5868","DOI":"10.1073\/pnas.0801775105","article-title":"Artificial miRNAs mitigate shRNA-mediated toxicity in the brain: implications for the therapeutic development of RNAi","volume":"105","author":"McBride","year":"2008","journal-title":"PNAS"},{"key":"2019112003002055700_B36","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1089\/hum.2017.199","article-title":"Artificial miRNAs reduce human mutant Huntingtin throughout the striatum in a transgenic sheep model of Huntington's disease","volume":"29","author":"Pfister","year":"2018","journal-title":"Hum. 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Med."},{"key":"2019112003002055700_B40","doi-asserted-by":"crossref","first-page":"82","DOI":"10.3389\/fncel.2017.00082","article-title":"Reduction of Huntington's Disease RNA Foci by CAG Repeat-Targeting Reagents","volume":"11","author":"Urbanek","year":"2017","journal-title":"Front Cell Neurosci."},{"key":"2019112003002055700_B41","doi-asserted-by":"crossref","first-page":"1759","DOI":"10.1038\/mt.2015.128","article-title":"Huntingtin haplotypes provide prioritized target panels for allele specific silencing in huntington disease patients of european ancestry","volume":"23","author":"Kay","year":"2015","journal-title":"Mol. Ther."},{"key":"2019112003002055700_B42","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/j.ajhg.2009.02.003","article-title":"CAG expansion in the Huntington disease gene is associated with a specific and targetable predisposing haplogroup","volume":"84","author":"Warby","year":"2009","journal-title":"Am. J. Hum. Genet."},{"key":"2019112003002055700_B43","doi-asserted-by":"crossref","first-page":"2178","DOI":"10.1038\/mt.2011.201","article-title":"Potent and selective antisense oligonucleotides targeting single-nucleotide polymorphisms in the Huntington disease gene \/ allele-specific silencing of mutant huntingtin","volume":"19","author":"Carroll","year":"2011","journal-title":"Mol. 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Genet.: EJHG"},{"key":"2019112003002055700_B51","doi-asserted-by":"crossref","first-page":"e1006846","DOI":"10.1371\/journal.pgen.1006846","article-title":"Elimination of huntingtin in the adult mouse leads to progressive behavioral deficits, bilateral thalamic calcification, and altered brain iron homeostasis","volume":"13","author":"Dietrich","year":"2017","journal-title":"PLos Genet."},{"key":"2019112003002055700_B52","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1038\/81593","article-title":"Inactivation of Hdh in the brain and testis results in progressive neurodegeneration and sterility in mice","volume":"26","author":"Dragatsis","year":"2000","journal-title":"Nat. Genet."},{"key":"2019112003002055700_B53","doi-asserted-by":"crossref","first-page":"2307","DOI":"10.1056\/NEJMoa1900907","article-title":"Targeting Huntingtin Expression in Patients with Huntington's Disease","volume":"380","author":"Tabrizi","year":"2019","journal-title":"N. Engl. J. 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