Intrabody Gene Therapy Ameliorates Motor, Cognitive, and Neuropathological Symptoms in Multiple Mouse Models of Huntington's Disease

摘要: Huntington's disease (HD) is an autosomal dominant neurodegenerative resulting from the expansion of a glutamine repeat in huntingtin (Htt) protein. Current therapies are directed at managing symptoms such as chorea and psychiatric disturbances. In effort to develop therapy prevention we investigated utility highly specific, anti-Htt intracellular antibodies (intrabodies). We previously showed that V_(L)12.3, intrabody recognizing N terminus Htt, Happ1, proline-rich domain both reduce mHtt-induced toxicity aggregation cell culture brain slice models HD. Due different mechanisms action these two intrabodies, then tested brains five mouse HD using chimeric adeno-associated virus 2/1 (AAV2/1) vector with modified CMV enhancer/chicken β-actin promoter. V_(L)12.3 treatment, while beneficial lentiviral model HD, has no effect on YAC128 actually increases severity phenotype mortality R6/2 model. contrast, Happ1 treatment confers significant effects variety assays motor cognitive deficits. also strongly ameliorates neuropathology found lentiviral, R6/2, N171-82Q, YAC128, BACHD Moreover, significantly prolongs life span N171-82Q mice. These results indicate increasing turnover mHtt AAV-Happ1 gene represents specific effective diverse