Intravitreal administration of HA-1077, a ROCK inhibitor, improves retinal function in a mouse model of huntington disease
| Autor: | Yong Huang, Michael T. Matthes, Douglas Yasumura, Matthew M. LaVail, Mei Li, Francis C. Szoka, Aye Aye K. Ma, Gregory Nielson, Haidong Yang, Marc I. Diamond |
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| Rok vydání: | 2012 |
| Předmět: |
Retinal degeneration
Pathology Huntingtin Mouse lcsh:Medicine Gene Expression Pharmacology Mice Profilins 0302 clinical medicine 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine Phosphorylation lcsh:Science Rho-associated protein kinase 0303 health sciences Huntingtin Protein rho-Associated Kinases Multidisciplinary medicine.diagnostic_test Neurodegenerative Diseases Animal Models Polyglutamine tract 3. Good health medicine.anatomical_structure Huntington Disease Neurology Autosomal Dominant Retinal Cone Photoreceptor Cells Medicine Retinal Disorders Female Immunohistochemical Analysis Research Article medicine.medical_specialty Drugs and Devices Drug Research and Development Clinical Research Design Preclinical Models Central nervous system Immunology Nerve Tissue Proteins Biology Retina 03 medical and health sciences Model Organisms In vivo medicine Electroretinography Animals Animal Models of Disease Protein Kinase Inhibitors 030304 developmental biology Clinical Genetics lcsh:R medicine.disease Disease Models Animal Ophthalmology Liposomes Immunologic Techniques lcsh:Q Dementia 030217 neurology & neurosurgery |
| Zdroj: | PLoS ONE PLoS ONE, Vol 8, Iss 2, p e56026 (2013) |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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