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Intravitreal administration of HA-1077, a ROCK inhibitor, improves retinal function in a mouse model of huntington disease.

Li M, Yasumura D, Ma AA, Matthes MT, Yang H, Nielson G, Huang Y, Szoka FC, Lavail MM, Diamond MI - PLoS ONE (2013)

Bottom Line: It is caused by an expanded polyglutamine tract in huntingtin (Htt).ROCK is thus a therapeutic target in HD.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Washington University in St. Louis, St. Louis, Missouri, USA.

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.

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Cone photoreceptors are lost in R6/2 mice.Cone counts in 10 microscopic fields of 2–5 retinas at each age of R6/2 and wild-type (WT) mice. The average number of cones is similar in the R6/2 and WT mice at 6–8 weeks of age, but there is a reduction in the number of cones in R6/2 mice of about 44% at 10–11 weeks and of about 55% at 18–19 weeks of age. *p<0.05; **p<5×10−9 by student t-test. Error bars represent S.E.M.
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pone-0056026-g004: Cone photoreceptors are lost in R6/2 mice.Cone counts in 10 microscopic fields of 2–5 retinas at each age of R6/2 and wild-type (WT) mice. The average number of cones is similar in the R6/2 and WT mice at 6–8 weeks of age, but there is a reduction in the number of cones in R6/2 mice of about 44% at 10–11 weeks and of about 55% at 18–19 weeks of age. *p<0.05; **p<5×10−9 by student t-test. Error bars represent S.E.M.

Mentions: The early decrease in cone function led us to examine the retinas for evidence of loss of cones. By counting cone nuclei in the retinas of R6/2 and wild-type retinas, we found that the number was virtually the same in both genotypes at 6–8 weeks of age. However, at 10–11 weeks and 18–19 weeks of age, the number of cones was reduced from normal by about 44% and 55%, respectively (Fig. 4). This method of counting cones has been effective and accurate in many studies of mouse retinal degeneration [13], [14], [20], [21].


Intravitreal administration of HA-1077, a ROCK inhibitor, improves retinal function in a mouse model of huntington disease.

Li M, Yasumura D, Ma AA, Matthes MT, Yang H, Nielson G, Huang Y, Szoka FC, Lavail MM, Diamond MI - PLoS ONE (2013)

Cone photoreceptors are lost in R6/2 mice.Cone counts in 10 microscopic fields of 2–5 retinas at each age of R6/2 and wild-type (WT) mice. The average number of cones is similar in the R6/2 and WT mice at 6–8 weeks of age, but there is a reduction in the number of cones in R6/2 mice of about 44% at 10–11 weeks and of about 55% at 18–19 weeks of age. *p<0.05; **p<5×10−9 by student t-test. Error bars represent S.E.M.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3569418&req=5

pone-0056026-g004: Cone photoreceptors are lost in R6/2 mice.Cone counts in 10 microscopic fields of 2–5 retinas at each age of R6/2 and wild-type (WT) mice. The average number of cones is similar in the R6/2 and WT mice at 6–8 weeks of age, but there is a reduction in the number of cones in R6/2 mice of about 44% at 10–11 weeks and of about 55% at 18–19 weeks of age. *p<0.05; **p<5×10−9 by student t-test. Error bars represent S.E.M.
Mentions: The early decrease in cone function led us to examine the retinas for evidence of loss of cones. By counting cone nuclei in the retinas of R6/2 and wild-type retinas, we found that the number was virtually the same in both genotypes at 6–8 weeks of age. However, at 10–11 weeks and 18–19 weeks of age, the number of cones was reduced from normal by about 44% and 55%, respectively (Fig. 4). This method of counting cones has been effective and accurate in many studies of mouse retinal degeneration [13], [14], [20], [21].

Bottom Line: It is caused by an expanded polyglutamine tract in huntingtin (Htt).ROCK is thus a therapeutic target in HD.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Washington University in St. Louis, St. Louis, Missouri, USA.

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.

Show MeSH
Related in: MedlinePlus