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We show that expression of a mutant human huntingtin exon-1-GFP fusion construct results in nonspecific gene dysregulation that is significantly reduced by 50% due to coexpression of INT41, an intrabody specific for the proline-rich region of the huntingtin protein. Using stable PC12 cell lines expressing either inducible human mutant huntingtin (mHtt, Q73) or normal huntingtin (nHtt, Q23), we investigated the effect of rAAV6-INT41, an adeno-associated virus vector with the INT41 coding sequence, on the subcellular distribution of Htt. Compartmental fractionation 8 days after induction of Htt showed a 6-fold increased association of a dominate N-terminal mHtt fragment with DNA compared to N-terminal nHtt. Transduction with rAAV6-INT41 reduced DNA binding of N-terminal mHtt 6.5-fold in the nucleus and reduced nuclear translocation of the detected fragments. Subsequently, when rAAV6-INT41 is delivered to the striatum in the R6\/2 mouse model, treated female mice exhibited executive function statistically indistinguishable from wild type, accompanied by reductions in Htt aggregates in the striatum, suggesting that rAAV6-INT41 is promising as a gene therapy for Huntington\u2019s disease.<\/jats:p>","DOI":"10.1155\/2016\/7120753","type":"journal-article","created":{"date-parts":[[2016,8,10]],"date-time":"2016-08-10T21:03:51Z","timestamp":1470863031000},"page":"1-10","source":"Crossref","is-referenced-by-count":13,"title":["An Intrabody Drug (rAAV6-INT41) Reduces the Binding of N-Terminal Huntingtin Fragment(s) to DNA to Basal Levels in PC12 Cells and Delays Cognitive Loss in the R6\/2 Animal Model"],"prefix":"10.1155","volume":"2016","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6942-2429","authenticated-orcid":true,"given":"I. Alexandra","family":"Amaro","sequence":"first","affiliation":[{"name":"Vybion Inc., P.O. 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