This suggested that this might be the optimal window at which to monitor effects of a putative disease modifier. The eye is a uniquely accessible CNS region to assess modifiers of pathology and neural dysfunction. It is possible readily to deliver experimental compounds without concern for bioavailability or systemic toxicity. We have previously described the neuroprotection afforded by Y-27632 in Drosophila and in R6/2 mice with systemic administration. HA-1077 is a ROCK inhibitor approved for clinical use in Japan. It is employed to suppress vasospasm in subarachnoid hemorrhage. We have previously observed that HA-1077 is more effective than Y- 27632 in suppressing phosphorylation of profilin at Ser-137. It has a chemical structure distinct from Y-27632, and thus also serves as an additional validation of the putative target, ROCK. Preliminary experiments revealed that the half-life of HA-1077 injected directly into the eye was less than 24 hrs, CP 775146 indicating that a more sustained release would be necessary. To improve the bioavailability of HA-1077, we BHPI packaged it into liposomes using palmitoyloleoylphosphatidylcholine and cholesterol with remote loading approaches. This method of drug delivery has been shown to provide sustained release within the intra-ocular space over several weeks. This study used ERG as a rapid, non-invasive measure of neuronal function in the R6/2 mouse model of HD to test a candidate therapeutic pathway. To begin, we established the characteristics of the progressive retinal pathology in R6/2 mice. We observed reduced photopic ERG responses at all ages examined, and a steady decline between 6 and 11 weeks of age. This was accompanied by loss of cone photoreceptors beginning at 10 weeks of age, at which time a progressive disorganization began in the outer retina. This roughly parallels decreases in rotarod performance in this line that we have previously observed in our laboratory. By packaging HA-1077 within liposomes, we were able to deliver the compound on a sustained basis following a single intravitreal injection. We treated two cohorts of animals with different doses of HA-1077, using injection of the contralateral eye with empty liposomes as an internal control. This, coupled with the rapid ERG changes, allowed us to reduce the time and number of animals required to carry out the trial versus a conventional approach. HA-1077 treatment reduced the amount of phospho-profilin in the retina, indicating that we were hitting our therapeutic target. Chronic treatment with a single injection of HA-1077 improved photopic ERG response amplitudes by 40�C60%. These data indicate that ROCK inhibition reduces expanded Htt toxicity, possibly by inhibiting profilin phosphorylation. Testing of lead compounds in mice is expensive, time consuming and labor-intensive.