, 2005). Irrespective of the many mechanistically divergent proposals for the underlying toxicity of expanded huntingtin, Alectinib order a therapy aimed at diminishing the synthesis of the toxic mutant protein is an approach that will directly target the primary disease mechanism(s), as long as it is effective in the key HD-affected cells and any coincident suppression of wild-type huntingtin is tolerated. Gene silencing strategies that suppress the synthesis of huntingtin that could be deployed as potential therapeutics

include virally encoded short-hairpin RNAs (shRNAs) or microRNAs (miRNAs) (Franich et al., 2008, Harper et al., 2005, Machida et al., 2006, McBride et al., 2008 and Rodriguez-Lebron et al., 2005), as well as direct infusion of synthetic siRNAs (DiFiglia et al., 2007 and Wang et al., 2005). In their current forms, each of these agents needs to be delivered by direct intraparenchymal injections, and therapeutic correction is limited to only a small portion of the striatum immediately adjacent to the sites of injection (Boudreau et al., 2009, DiFiglia et al., 2007, Drouet et al., 2009, Harper et al., 2005 and McBride et al., 2008). While the striatum is particularly vulnerable to mutant huntingtin-mediated toxicity, huntingtin is ubiquitously expressed (Hoogeveen et al., 1993), www.selleckchem.com/products/LY294002.html and selective expression

of mutant huntingtin in striatal neurons is not sufficient to cause locomotor deficits or neuropathology in rodents (Gu et al., 2007). To date, the collective evidence strongly supports a disease mechanism in which mutant huntingtin expression in multiple cell Edoxaban types within at least the striatum and cortex is likely required for disease development and progression. Indeed, cortical thinning is observed in human patients prior to the onset of symptoms (Rosas et al., 2002 and Rosas et al., 2006), and by endstage, typically more than 30% of an HD patient’s brain mass is lost (de la Monte et al., 1988). Finally, the human striatum

accounts for only ∼1% of the total brain volume, indicating the disease is affecting other areas of the brain. All of this evidence suggests that a fully effective treatment of HD will likely require targeting multiple brain regions. An alternative approach to preceding efforts for achieving reduction in huntingtin synthesis is infusion of single stranded antisense oligonucleotides (ASOs). ASOs base pair with target mRNAs and direct their catalytic degradation through the action of RNase H, an endogenous enzyme present in most mammalian cells (Cerritelli and Crouch, 2009 and Crooke, 1999). Phosphorothioate-modified chimeric ASOs with 2′-O-methoxyethyl (MOE) and deoxynucleotide (DNA) sugar modifications are water soluble and resistant to exonucleases (Bennett and Swayze, 2010, Henry et al., 2001 and Yu et al., 2004), and RNAs paired with them are efficiently degraded by RNase H.