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

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease resulting from the expansion of a glutamine repeat in the huntingtin (Htt) protein. Current therapies are directed at managing symptoms such as chorea and psychiatric disturbances. In an effort to develop a therapy directed at disease prevention we investigated the utility of highly specific, anti-Htt intracellular antibodies (intrabodies). We previously showed that VL12.3, an intrabody recognizing the N terminus of Htt, and Happ1, an intrabody recognizing theproline-richdomainofHtt, both reducemHtt-induced toxicity andaggregation in cell culture andbrain slicemodels ofHD.Due to the different mechanisms of action of these two intrabodies, we then tested both in the brains of five mouse models of HD using a chimeric adeno-associated virus 2/1 (AAV2/1) vectorwith amodifiedCMVenhancer/chicken-actinpromoter.VL12.3 treatment,while beneficial in a lentiviralmodel of HD, has no effect on the YAC128HDmodel and actually increases severity of phenotype andmortality in the R6/2 HDmodel. In contrast, Happ1 treatment confers significant beneficial effects in a variety of assays ofmotor and cognitive deficits. Happ1 also strongly ameliorates the neuropathology found in the lentiviral, R6/2, N171-82Q, YAC128, and BACHD models of HD. Moreover, Happ1 significantly prolongs the life span of N171-82Q mice. These results indicate that increasing the turnover of mHtt using AAV-Happ1 gene therapy represents a highly specific and effective treatment in diverse mouse models of HD