A strong point of the current study is the use of three distinct transgenic

mouse models of HD, three Htt-targeting ASOs, and seven independent preclinical trials to demonstrate the efficacy of ASOs in abating disease phenotypes in vivo. In R6/2, an mHtt-exon1 transgenic mouse model that exhibits aggressive and lethal disease course, 4 week infusion of ASOs at a symptomatic stage leads to 60% lowering of mHtt exon1, amelioration of brain atrophy, and prolonged survival. However, the nuclear inclusion formation was not modified by ASO treatment, suggesting only partial improvement of disease pathology in this model. The therapeutic efficacy of Htt ASOs was more thoroughly investigated in two full-length human mHtt genomic transgenic mouse models, YAC128 and BACHD. In the YAC128 model, which expresses human full-length mHtt with 128Q (Slow et al., 2003), 2 week ASO infusion selleckchem results in 80% mHtt lowering and E7080 cost significant improvement of motor coordination on rotarod test. However, treatment initiated at a later and more symptomatic age (6 months) leads only to a trend, but not statistically significant improvement, suggesting that earlier ASO treatment may confer better therapeutic effect, at least in this model. The most in-depth preclinical assessments the authors performed with ASOs were conducted in BACHD mice, which express full-length human mHtt with 97Q under endogenous genomic

regulation (Gray et al., 2008). BACHD mice exhibit progressive motor and psychiatric-like behavioral deficits (e.g., anxiety), selective cortical and striatal atrophy, and confer good statistical power to detect disease modification (Gray et al., 2008). With 2 week intraventricular infusion of human-selective ASOs in BACHD mice at 6 months of age, the treated mice show significant improvement in motor coordination and open-field exploration and reduction in anxiety at 8–12 months of age. To further evaluate the potential lasting beneficial effects of transient ASO therapy, Kordasiewicz et al. (2012) performed a second BACHD

trial to infuse ASOs at 6 months and assayed these mice up to 15 months of age. Surprisingly, even 9 months after ASO infusion and 5 months after mHtt level returns to baseline, ASO-treated BACHD mice still show sustained benefits Mannose-binding protein-associated serine protease in motor and anxiety behaviors. The results from neuropathology are somewhat mixed, with ASO-treated BACHD mice showing fewer mHtt aggregates, but no rescue of the brain atrophy phenotype. The latter finding raises some questions about whether earlier ASO delivery or a repeated treatment regimen may be necessary to ameliorate neurodegeneration. In this tour de force preclinical study, Kordasiewicz et al. (2012) also addressed the issue of the safety and efficacy of targeting endogenous Htt. They showed that the infusion of ASOs against both human and murine Htt into BACHD mice, achieving up to a 75% reduction of human mHtt and murine wild-type Htt, did not alter therapeutic benefits.