5 or postnatal

day 5 (Dragatsis et al., 2000) and in cultured neuronal cells (Gauthier et al., 2004 and Zuccato et al., 2003). However, no evidence has demonstrated toxicity following suppression of huntingtin in the adult brain. In fact, simultaneous suppression of mutant and normal huntingtin by 60% in the adult rodent striatum, and suppression of normal huntingtin by 45% in the nonhuman primate striatum were both well tolerated (Boudreau et al., 2009, Drouet et al., 2009 and McBride et al., 2011). Our ASO approach has extended these earlier efforts: reducing huntingtin levels by 75% throughout the CNS neither exacerbates disease nor lessens the therapeutic benefit from suppression of mutant huntingtin. Moreover, suppression of normal huntingtin Selleck PD-1/PD-L1 inhibitor 2 for up to 3 months (the latest time assessed) in healthy primates was well tolerated. These findings provide experimental support for the existence of a therapeutic window for safe, yet efficacious, transient suppression with a nonallele selective ASO approach. They also lay the foundation for sustained phenotypic reversal from

allele selective reduction of mutant huntingtin with mutant CAG targeting ASOs (Gagnon et al., 2010 and Hu et al., 2009) or ASOs that target single nucleotide polymorphisms present in the mutant allele (Carroll et al., 2011, Liu et al., 2008 and Pfister et al., 2009). Finally, our evidence Bay 11-7085 has provided an initial demonstration that Selleck GSK1120212 transient suppression of huntingtin can be sufficient to ameliorate disease for an extended period of time. For diseases like Huntington’s where a mutant protein product is tolerated for decades prior to disease onset, this finding opens up the provocative possibility that transient suppression

of huntingtin can lead to a prolonged effect in patients. Indeed, this raises the prospect that a transient decrease in huntingtin synthesis may allow for clearance of disease causing species that form only very slowly and may then take weeks or months to reform. If so, then a single transient application of ASOs may “reset the disease clock,” providing a benefit long after huntingtin suppression has ended. Of obvious interest in this regard is to use the rodent examples to determine how long the beneficial effect can persist after a single ASO injection. BACHD animals were acquired from William Yang (Gray et al., 2008). BACHD mice were maintained on the congenic FVB/N background, and only female mice were used. YAC128 mice (Hodgson et al., 1999) were obtained from the Genzyme colony at Charles River Laboratories and maintained on the congenic FVB/NJ background. R6/2 animals (Mangiarini et al., 1996) were obtained from Jackson laboratories and maintained by crossing transgene positive males with F1 (CBA × C57BL6) females (CAG repeats were maintained between 110 and 135).