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Intravitreal administration of HA-1077, a ROCK inhibitor, improves retinal function in a mouse model of huntington
Mei Li1, Douglas Yasumura, Aye Aye K Ma
1Department of Neurology, Washington University in St. Louis, St. Louis, Missouri, USA.
Insights
Huntington disease (HD) therapies are advanced by targeting rho-associated kinase (ROCK). A ROCK inhibitor, HA-1077, improved retinal function in R6/2 HD mice, validating the retina as a neurodegenerative disease model.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Huntington disease (HD) is an inherited neurodegenerative disorder caused by expanded polyglutamine tracts in huntingtin (Htt).
- Therapy development for HD is challenged by a lack of targets and complex in vivo testing.
- The R6/2 mouse model exhibits neural dysfunction, including retinal degeneration, making it suitable for pre-clinical studies.
Purpose of the Study:
- To characterize the progressive retinopathy in R6/2 mice to identify an optimal treatment window.
- To evaluate the efficacy of a clinically approved rho-associated kinase (ROCK) inhibitor, HA-1077, delivered intravitreally for HD treatment.
- To establish the retina as a viable readout for central nervous system (CNS) function in neurodegenerative disease models.
Main Methods:
- Characterization of retinopathy progression in R6/2 mice from 6 to 19 weeks of age.
- Intravitreal administration of HA-1077 via liposome-mediated drug delivery in R6/2 and wild-type mice.
- Assessment of retinal function using photopic and flicker electroretinography (ERG).
Main Results:
- HA-1077 treatment significantly increased photopic and flicker ERG response amplitudes in R6/2 mice.
- No significant changes in ERG amplitudes were observed in wild-type littermate controls treated with HA-1077.
- The study established an optimal treatment window for intervention in the R6/2 mouse model.
Conclusions:
- Targeting ROCK with HA-1077 demonstrates in vivo therapeutic efficacy in a mouse model of Huntington disease.
- Liposome-mediated intravitreal delivery of HA-1077 is a feasible approach for treating retinal dysfunction in HD models.
- The retina serves as a sensitive and accessible readout for evaluating therapeutic interventions in neurodegenerative diseases like HD.
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.
