Three groups have forged an important collaboration to test the utility of antisense oligonucleotides (ASOs) as a therapeutic modality for the treatment of Huntington's disease (HD), a fatal neurodegenerative disease manifesting in ~75,000 individuals in the United States and Europe alone.1 HD is one of a group of dominantly inherited neurodegenerative diseases caused by polyglutamine repeat expansion. In the case of HD, the mutation induces a toxic gain-of-function upon the huntingtin protein, perturbing numerous pathways at the cellular level, and inducing motor and psychiatric symptoms in patients. The groups, led by Don Cleveland of UC San Diego, La Jolla, CA, Lamya Shihabuddin at Genzyme (Framingham, MA), and Frank Bennett at Isis Pharmaceuticals (Carlsbad, CA), screened a series of ASOs targeting mouse and/or human huntingtin, and then rigorously evaluated them in three established animal models of HD and in naive nonhuman primates.2 The ASOs are a strategy to target huntingtin mRNAs for destruction, thereby reducing huntingtin protein levels. In mice, the ASOs were delivered into the ventricles of the brain using pumps, and the effects of the ASOs on behavior and huntingtin protein levels monitored. The infused ASOs distributed widely in rodent brain, lowering huntingtin mRNA and protein. In an acute, short-lived HD model, ASO delivery extended life span by several days and increased brain mass. In two additional models expressing full-length mutant transgenic alleles, the ASOs improved motor function. Intriguingly, and one of the crucial findings of the study, was that the clinical benefit outlasted the duration of huntingtin protein suppression. The respite from the mutant protein, even in the setting of reduced levels of wild-type huntingtin, was remarkably beneficial. In the nonhuman primates, ASOs infused into the spinal canal resulted in notable bioactivity in specific cortical regions as well as cervical spinal cord, and again knockdown of huntingtin persisted well beyond the ASO delivery period. This work complements prior rodent studies demonstrating the efficacy of silencing huntingtin using RNA interference-based approaches,3,4,5,6,7 and the short-term safety of reducing huntingtin expression in the nonhuman primate brain.8 In those earlier works, sustained expression of inhibitory RNAs targeting mutant huntingtin alone3 or both mutant and the wild-type alleles4,6 from recombinant viral vectors provided therapeutic benefit throughout the striatum and significantly improved motor phenotypes. Cumulatively, the data show that reduction of both the mutant and wild-type alleles (in rodents), or normal huntingtin (in the adult nonhuman primate brain) is well tolerated. Another critical issue that had not been addressed previously was the reversibility of the disease process using these huntingtin-lowering approaches. Studies in transgenic models suggested that this was possible however. Experiments in Renee Hen's lab by Ai Yamamoto9 showed that suppression of mutant huntingtin after onset of histological and behavioral phenotypes improved these same disease manifestations. Turning “off” the disease allele even after there was obvious striatal loss was also beneficial.10 Here, the ASOs, which are distributed broadly in the rodent brain after delivery into the ventricles, also improved symptoms when delivered after disease onset. And importantly, they provided for benefit well after mRNA and protein levels returned to normal. As this technology transitions into the clinic for HD therapy, the major hurdle remains delivery and distribution to a large primate brain. ASO distribution using immunohistochemical methods appears broad after a 21-day intrathecal infusion into the nonhuman primate cerebrospinal fluid. However, the brain areas showing the most robust knockdown were the spinal cord, followed by the posterior and anterior cortex. There was very modest (nonsignificant) knockdown in the caudate (~20%), a region dramatically affected in HD. It remains to be tested whether the ~20% reduction of huntingtin in the caudate will provide clinical benefit. The putamen also suffers from extensive cell loss in HD, but no data was presented as to whether the ASOs achieve sufficient knockdown in this region. Future studies in emerging models of HD in sheep11 or nonhuman primates12 will help address the utility of this exciting approach to treating HD.