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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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Outer nuclear layer thickness is similar in R6/2 and wild-type mice.The mean outer nuclear layer (ONL) of the retinas of R6/2 and wild-type (WT) mice are virtually identical at all ages studied. Mean ± SEM of 3–7 mice of each genotype at each age.
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pone-0056026-g002: Outer nuclear layer thickness is similar in R6/2 and wild-type mice.The mean outer nuclear layer (ONL) of the retinas of R6/2 and wild-type (WT) mice are virtually identical at all ages studied. Mean ± SEM of 3–7 mice of each genotype at each age.

Mentions: The R6/2 mice were indistinguishable from normal by high-resolution histology at 6–8 weeks of age (Fig. 1D). However, by 10–11 weeks, they began to have perturbations of the ONL (Fig. 1E), and thereafter developed the appearance thoroughly described by Helmlinger et al. [3] and Petrasch-Parwez et al. [4]. This included a focal irregular and ‘wavy’ ONL (Fig. 1F) predominantly located in the central-to-equatorial retina. While these undulations (retinal folds) were found in all of 10 mice examined at 18–19 weeks of age, they occupied a relatively small portion of the retinal length (7.4±4.4%, n = 10, range of 3–18%). Most of the ONL of these retinas had a normal appearance (Fig. 1G), but at all ages from 10–19 weeks, there was a disruption and shortening of the photoreceptor outer segments (Fig. 1E–G); some vacuoles in the interphotoreceptor space in the outer segment layer (Fig. 1F–G); some separation of the retina from retinal pigment epithelium (Fig. 1D); and displacement of some photoreceptor nuclei into the outer segment layer (not shown). The extent of the disorganization of the ONL became progressively more extensive in character and distribution by 18–19 weeks of age, but as reported previously for 10 weeks of age, the overall ONL did not become reduced in thickness at any age examined (Fig. 2), so relatively few rod nuclei were lost. Measurement of the ONL thickness is the most accurate and accepted measure of the relative number of photoreceptor nuclei [18]. It should be noted that the mouse ONL comprises about 97% rod nuclei and only 3% cone nuclei [19], so that any loss of cones would not be detected by ONL thickness measurements.


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)

Outer nuclear layer thickness is similar in R6/2 and wild-type mice.The mean outer nuclear layer (ONL) of the retinas of R6/2 and wild-type (WT) mice are virtually identical at all ages studied. Mean ± SEM of 3–7 mice of each genotype at each age.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3569418&req=5

pone-0056026-g002: Outer nuclear layer thickness is similar in R6/2 and wild-type mice.The mean outer nuclear layer (ONL) of the retinas of R6/2 and wild-type (WT) mice are virtually identical at all ages studied. Mean ± SEM of 3–7 mice of each genotype at each age.
Mentions: The R6/2 mice were indistinguishable from normal by high-resolution histology at 6–8 weeks of age (Fig. 1D). However, by 10–11 weeks, they began to have perturbations of the ONL (Fig. 1E), and thereafter developed the appearance thoroughly described by Helmlinger et al. [3] and Petrasch-Parwez et al. [4]. This included a focal irregular and ‘wavy’ ONL (Fig. 1F) predominantly located in the central-to-equatorial retina. While these undulations (retinal folds) were found in all of 10 mice examined at 18–19 weeks of age, they occupied a relatively small portion of the retinal length (7.4±4.4%, n = 10, range of 3–18%). Most of the ONL of these retinas had a normal appearance (Fig. 1G), but at all ages from 10–19 weeks, there was a disruption and shortening of the photoreceptor outer segments (Fig. 1E–G); some vacuoles in the interphotoreceptor space in the outer segment layer (Fig. 1F–G); some separation of the retina from retinal pigment epithelium (Fig. 1D); and displacement of some photoreceptor nuclei into the outer segment layer (not shown). The extent of the disorganization of the ONL became progressively more extensive in character and distribution by 18–19 weeks of age, but as reported previously for 10 weeks of age, the overall ONL did not become reduced in thickness at any age examined (Fig. 2), so relatively few rod nuclei were lost. Measurement of the ONL thickness is the most accurate and accepted measure of the relative number of photoreceptor nuclei [18]. It should be noted that the mouse ONL comprises about 97% rod nuclei and only 3% cone nuclei [19], so that any loss of cones would not be detected by ONL thickness measurements.

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