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We have developed a microRNA targeting human HTT that is delivered in an adeno-associated serotype 5 viral vector (AAV5-miHTT), and here use animal behaviour, MRI, non-invasive proton magnetic resonance spectroscopy and striatal RNA sequencing as outcome measures in preclinical mouse studies of AAV5-miHTT.<\/jats:p>\n               <jats:p>The effects of AAV5-miHTT treatment were evaluated in homozygous Q175FDN mice, a mouse model of Huntington\u2019s disease with severe neuropathological and behavioural phenotypes. Homozygous mice were used instead of the more commonly used heterozygous strain, which exhibit milder phenotypes. Three-month-old homozygous Q175FDN mice, which had developed acute phenotypes by the time of treatment, were injected bilaterally into the striatum with either formulation buffer (phosphate-buffered saline + 5% sucrose), low dose (5.2 \u00d7 109 genome copies\/mouse) or high dose (1.3 \u00d7 1011 genome copies\/mouse) AAV5-miHTT. Wild-type mice injected with formulation buffer served as controls. Behavioural assessments of cognition, T1-weighted structural MRI and striatal proton magnetic resonance spectroscopy were performed 3 months after injection, and shortly afterwards the animals were sacrificed to collect brain tissue for protein and RNA analysis. Motor coordination was assessed at 1-month intervals beginning at 2 months of age until sacrifice.<\/jats:p>\n               <jats:p>Dose-dependent changes in AAV5 vector DNA level, miHTT expression and mutant HTT were observed in striatum and cortex of AAV5-miHTT-treated Huntington\u2019s disease model mice. This pattern of microRNA expression and mutant HTT lowering rescued weight loss in homozygous Q175FDN mice but did not affect motor or cognitive phenotypes. MRI volumetric analysis detected atrophy in four brain regions in homozygous Q175FDN mice, and treatment with high dose AAV5-miHTT rescued this effect in the hippocampus. Like previous magnetic resonance spectroscopy studies in Huntington\u2019s disease patients, decreased total N-acetyl aspartate and increased myo-inositol levels were found in the striatum of homozygous Q175FDN mice. These neurochemical findings were partially reversed with AAV5-miHTT treatment. Striatal transcriptional analysis using RNA sequencing revealed mutant HTT-induced changes that were partially reversed by HTT lowering with AAV5-miHTT. Striatal proton magnetic resonance spectroscopy analysis suggests a restoration of neuronal function, and striatal RNA sequencing analysis shows a reversal of transcriptional dysregulation following AAV5-miHTT in a homozygous Huntington\u2019s disease mouse model with severe pathology.<\/jats:p>\n               <jats:p>The results of this study support the use of magnetic resonance spectroscopy in HTT-lowering clinical trials and strengthen the therapeutic potential of AAV5-miHTT in reversing severe striatal dysfunction in Huntington\u2019s disease.<\/jats:p>","DOI":"10.1093\/brain\/awac458","type":"journal-article","created":{"date-parts":[[2022,12,12]],"date-time":"2022-12-12T17:42:38Z","timestamp":1670866958000},"page":"2298-2315","source":"Crossref","is-referenced-by-count":25,"title":["AAV5-miHTT-mediated huntingtin lowering improves brain health in a Huntington\u2019s disease mouse model"],"prefix":"10.1093","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9407-1245","authenticated-orcid":false,"given":"Sarah B","family":"Thomson","sequence":"first","affiliation":[{"name":"Department of Medical Genetics, Centre for Molecular Medicine & Therapeutics, University of British Columbia and BC Children\u2019s Hospital , Vancouver, BC V5Z4H4 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anouk","family":"Stam","sequence":"additional","affiliation":[{"name":"Department of Research & Development, uniQure Biopharma B.V. , 1105BP Amsterdam , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia","family":"Brouwers","sequence":"additional","affiliation":[{"name":"Department of Research & Development, uniQure Biopharma B.V. , 1105BP Amsterdam , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Fodale","sequence":"additional","affiliation":[{"name":"Department of Translational Biology, IRBM S.p.A. , Pomezia 00071 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Bresciani","sequence":"additional","affiliation":[{"name":"Department of Translational Biology, IRBM S.p.A. , Pomezia 00071 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Vermeulen","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Centre for Molecular Medicine & Therapeutics, University of British Columbia and BC Children\u2019s Hospital , Vancouver, BC V5Z4H4 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Mostafavi","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Centre for Molecular Medicine & Therapeutics, University of British Columbia and BC Children\u2019s Hospital , Vancouver, BC V5Z4H4 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terri L","family":"Petkau","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Centre for Molecular Medicine & Therapeutics, University of British Columbia and BC Children\u2019s Hospital , Vancouver, BC V5Z4H4 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Austin","family":"Hill","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Centre for Molecular Medicine & Therapeutics, University of British Columbia and BC Children\u2019s Hospital , Vancouver, BC V5Z4H4 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Yung","sequence":"additional","affiliation":[{"name":"UBC MRI Research Centre, Department of Radiology, University of British Columbia , Vancouver, BC V6T2B5 , 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