Huntington's disease (HD) is an autosomal dominant neurodegenerative disease 
caused by the expansion of a CAG trinucleotide repeat in exon 1 of the 
huntingtin (htt) gene. Emergence and progression of HD depend on continuous 
expression of mutant Huntingtin protein (Htt). Therefore, blocking expression of 
mutant Htt might be a promising therapeutic strategy. We generated a 
high-capacity adenoviral (HC-Ad) vector expressing a short hairpin RNA (shRNA) 
targeted to exon 1 of the htt gene. In vitro, this vector efficiently inhibited 
Htt expression in neuronal and nonneuronal cell lines. In addition, the number 
of Htt-immunoreactive (IR) aggregates, a hallmark of HD pathology, was 
significantly reduced after gene transfer with this vector. Importantly, the 
attenuation of aggregate formation by shRNA was observed in vivo after 
stereotaxic injection into the striatum of mouse models of HD. The vector was 
tested in two models: the R6/2 transgenic mouse model and a mouse model based on 
the local injection of an adenoviral vector expressing a truncated version of 
mutant Htt. In both models an efficient reduction in mutant Htt aggregate load 
measured by decreased Htt-IR aggregate formation was observed. Our results 
support the further development of shRNA for HD therapy.