Intravitreal Administration of HA-1077, a ROCK Inhibitor, Improves Retinal Function in a Mouse Model of Huntington Disease

Mei Li, Douglas Yasumura, Aye Aye K Ma, Michael T. Matthes, Haidong Yang, Gregory Nielson, Yong Huang, Francis C. Szoka, Matthew M. LaVail, Marc I. Diamond

Research output: Contribution to journalArticle

25 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere56026
JournalPLoS One
Volume8
Issue number2
DOIs
StatePublished - Feb 11 2013

Fingerprint

rho-Associated Kinases
Huntington Disease
Neurodegenerative diseases
phosphotransferases (kinases)
animal models
neurodegenerative diseases
Profilins
Neurodegenerative Diseases
therapeutics
home furnishings
Lead compounds
Therapeutics
retinal diseases
Retinal Degeneration
disease models
mice
Testing
Drug delivery
retina
Liposomes

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Intravitreal Administration of HA-1077, a ROCK Inhibitor, Improves Retinal Function in a Mouse Model of Huntington Disease. / Li, Mei; Yasumura, Douglas; Ma, Aye Aye K; Matthes, Michael T.; Yang, Haidong; Nielson, Gregory; Huang, Yong; Szoka, Francis C.; LaVail, Matthew M.; Diamond, Marc I.

In: PLoS One, Vol. 8, No. 2, e56026, 11.02.2013.

Research output: Contribution to journalArticle

Li, M, Yasumura, D, Ma, AAK, Matthes, MT, Yang, H, Nielson, G, Huang, Y, Szoka, FC, LaVail, MM & Diamond, MI 2013, 'Intravitreal Administration of HA-1077, a ROCK Inhibitor, Improves Retinal Function in a Mouse Model of Huntington Disease', PLoS One, vol. 8, no. 2, e56026. https://doi.org/10.1371/journal.pone.0056026
Li, Mei ; Yasumura, Douglas ; Ma, Aye Aye K ; Matthes, Michael T. ; Yang, Haidong ; Nielson, Gregory ; Huang, Yong ; Szoka, Francis C. ; LaVail, Matthew M. ; Diamond, Marc I. / Intravitreal Administration of HA-1077, a ROCK Inhibitor, Improves Retinal Function in a Mouse Model of Huntington Disease. In: PLoS One. 2013 ; Vol. 8, No. 2.
@article{337af175ca834e0397db023cc27ceead,
title = "Intravitreal Administration of HA-1077, a ROCK Inhibitor, Improves Retinal Function in a Mouse Model of Huntington Disease",
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.",
author = "Mei Li and Douglas Yasumura and Ma, {Aye Aye K} and Matthes, {Michael T.} and Haidong Yang and Gregory Nielson and Yong Huang and Szoka, {Francis C.} and LaVail, {Matthew M.} and Diamond, {Marc I.}",
year = "2013",
month = "2",
day = "11",
doi = "10.1371/journal.pone.0056026",
language = "English (US)",
volume = "8",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "2",

}

TY - JOUR

T1 - Intravitreal Administration of HA-1077, a ROCK Inhibitor, Improves Retinal Function in a Mouse Model of Huntington Disease

AU - Li, Mei

AU - Yasumura, Douglas

AU - Ma, Aye Aye K

AU - Matthes, Michael T.

AU - Yang, Haidong

AU - Nielson, Gregory

AU - Huang, Yong

AU - Szoka, Francis C.

AU - LaVail, Matthew M.

AU - Diamond, Marc I.

PY - 2013/2/11

Y1 - 2013/2/11

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84873682261&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84873682261&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0056026

DO - 10.1371/journal.pone.0056026

M3 - Article

VL - 8

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 2

M1 - e56026

ER -