title: Intravitreal administration of HA-1077, a ROCK inhibitor, improves retinal function in a mouse model of huntington disease.
abstract: Huntington disease (HD) is an inherited neurodegenerative disease that affects multiple brain regions. It is caused by an expanded polyglutamine tract in huntingtin (Htt). The development of therapies for HD and other neurodegenerative diseases has been hampered by multiple factors, including the lack of clear therapeutic targets, and the cost and complexity of testing lead compounds in vivo. The R6/2 HD mouse model is widely used for pre-clinical trials because of its progressive and robust neural dysfunction, which includes retinal degeneration. Profilin-1 is a Htt binding protein that inhibits Htt aggregation. Its binding to Htt is regulated by the rho-associated kinase (ROCK), which phosphorylates profilin at Ser-137. ROCK is thus a therapeutic target in HD. The ROCK inhibitor Y-27632 reduces Htt toxicity in fly and mouse models. Here we characterized the progressive retinopathy of R6/2 mice between 6-19 weeks of age to determine an optimal treatment window. We then tested a clinically approved ROCK inhibitor, HA-1077, administered intravitreally via liposome-mediated drug delivery. HA-1077 increased photopic and flicker ERG response amplitudes in R6/2 mice, but not in wild-type littermate controls. By targeting ROCK with a new inhibitor, and testing its effects in a novel in vivo model, these results validate the in vivo efficacy of a therapeutic candidate, and establish the feasibility of using the retina as a readout for CNS function in models of neurodegenerative disease.
authors: Department of Neurology, Washington University in St. Louis, St. Louis, Missouri, USA.
authors: Mei
authors: M
authors: Li
authors: Douglas
authors: D
authors: Yasumura
authors: Aye Aye K
authors: AA
authors: Ma
authors: Michael T
authors: MT
authors: Matthes
authors: Haidong
authors: H
authors: Yang
authors: Gregory
authors: G
authors: Nielson
authors: Yong
authors: Y
authors: Huang
authors: Francis C
authors: FC
authors: Szoka
authors: Matthew M
authors: MM
authors: Lavail
authors: Marc I
authors: MI
authors: Diamond
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D004596:Electroretinography; D005260:Female; D015870:Gene Expression; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism*; D008081:Liposomes; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051304:Profilins / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D012160:Retina / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D017949:Retinal Cone Photoreceptor Cells / Q000187:drug effects / Q000378:metabolism; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D008081:Liposomes; D009419:Nerve Tissue Proteins; D051304:Profilins; D047428:Protein Kinase Inhibitors; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; C049347:fasudil