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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-mediated ERG responses in R6/2 mice are lower than normal at all ages examined.ERG analysis of 6–19 week old R6/2 and wild-type mice at each age (see results). The light-adapted photopic b-wave (Phot b, open diamonds) and flicker (Flicker, open circles) cone-mediated ERG responses are significantly lower in amplitude than age-matched wild-type mice (range in shaded area) at all ages, beginning at 6 weeks of age. The scotopic a-wave (Scot a; open inverted triangles) and the scotopic b-wave (Scot b; open triangles) are significantly lower than wild-type controls beginning only at 9 weeks of age. *P<0.05; **P<0.005; ***P<5×10−6 by student t-test. Error bars represent S.E.M.
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pone-0056026-g003: Cone-mediated ERG responses in R6/2 mice are lower than normal at all ages examined.ERG analysis of 6–19 week old R6/2 and wild-type mice at each age (see results). The light-adapted photopic b-wave (Phot b, open diamonds) and flicker (Flicker, open circles) cone-mediated ERG responses are significantly lower in amplitude than age-matched wild-type mice (range in shaded area) at all ages, beginning at 6 weeks of age. The scotopic a-wave (Scot a; open inverted triangles) and the scotopic b-wave (Scot b; open triangles) are significantly lower than wild-type controls beginning only at 9 weeks of age. *P<0.05; **P<0.005; ***P<5×10−6 by student t-test. Error bars represent S.E.M.

Mentions: To define the characteristics of ERG changes over time, we studied multiple R6/2 and age-matched wild-type mice at various ages. We examined mice at 6 weeks (WT n = 8, R6/2 n = 8), 7 weeks (WT n = 6, R6/2 n = 9), 8 weeks (WT n = 15, R6/2 n = 11), 9 weeks (WT n = 13, R6/2 n = 13) and 11 weeks (WT n = 19, R6/2 n = 16) by ERG. Scotopic ERG responses, which predominantly measure rod (dark-adapted) function, remained relatively stable throughout the early portions of disease, and did not differ significantly from control values until 9 weeks of age. Both the scotopic a-wave and b-waves were lower than controls then and thereafter (Fig. 3). By contrast, photopic ERG response amplitudes were significantly lower than normal at all ages, beginning by at least 6 weeks of age. These primarily cone-mediated (light-adapted) responses were found with photopic and flicker ERG measurements (Fig. 3). Thus, the cone-mediated retinal deficit was evident at about the same age as the behavioral motor dysfunction, but before any detectable changes in retinal histology.


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-mediated ERG responses in R6/2 mice are lower than normal at all ages examined.ERG analysis of 6–19 week old R6/2 and wild-type mice at each age (see results). The light-adapted photopic b-wave (Phot b, open diamonds) and flicker (Flicker, open circles) cone-mediated ERG responses are significantly lower in amplitude than age-matched wild-type mice (range in shaded area) at all ages, beginning at 6 weeks of age. The scotopic a-wave (Scot a; open inverted triangles) and the scotopic b-wave (Scot b; open triangles) are significantly lower than wild-type controls beginning only at 9 weeks of age. *P<0.05; **P<0.005; ***P<5×10−6 by student t-test. Error bars represent S.E.M.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3569418&req=5

pone-0056026-g003: Cone-mediated ERG responses in R6/2 mice are lower than normal at all ages examined.ERG analysis of 6–19 week old R6/2 and wild-type mice at each age (see results). The light-adapted photopic b-wave (Phot b, open diamonds) and flicker (Flicker, open circles) cone-mediated ERG responses are significantly lower in amplitude than age-matched wild-type mice (range in shaded area) at all ages, beginning at 6 weeks of age. The scotopic a-wave (Scot a; open inverted triangles) and the scotopic b-wave (Scot b; open triangles) are significantly lower than wild-type controls beginning only at 9 weeks of age. *P<0.05; **P<0.005; ***P<5×10−6 by student t-test. Error bars represent S.E.M.
Mentions: To define the characteristics of ERG changes over time, we studied multiple R6/2 and age-matched wild-type mice at various ages. We examined mice at 6 weeks (WT n = 8, R6/2 n = 8), 7 weeks (WT n = 6, R6/2 n = 9), 8 weeks (WT n = 15, R6/2 n = 11), 9 weeks (WT n = 13, R6/2 n = 13) and 11 weeks (WT n = 19, R6/2 n = 16) by ERG. Scotopic ERG responses, which predominantly measure rod (dark-adapted) function, remained relatively stable throughout the early portions of disease, and did not differ significantly from control values until 9 weeks of age. Both the scotopic a-wave and b-waves were lower than controls then and thereafter (Fig. 3). By contrast, photopic ERG response amplitudes were significantly lower than normal at all ages, beginning by at least 6 weeks of age. These primarily cone-mediated (light-adapted) responses were found with photopic and flicker ERG measurements (Fig. 3). Thus, the cone-mediated retinal deficit was evident at about the same age as the behavioral motor dysfunction, but before any detectable changes in retinal histology.

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