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Cited by 59Genetic Neurodegenerative DiseasesRetinal Development and DisordersLysosomal Storage Disorders Research

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

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Li, Mei, Yasumura, Douglas, Ma, Aye Aye K., Matthes, Michael T., Yang, Haidong, Nielson, Gregory, Huang, Yong, Szoka, Francis C. +2 more·2013·PLoS ONE
DOI 10.1371/journal.pone.0056026PMC PMC3569418
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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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  • Intravitreal application of the more potent ROCK inhibitor Fasudil rescues the progressive retinopathy in the same HD mouse model.

    “However, intravitreal application of the more potent ROCK inhibitor, Fasudil, was able to rescue the progressive retinopathy in the same HD mouse model [202].”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [202]

    The Introduction identifies HA-1077 as Fasudil, and the Results (Liposome-mediated drug delivery; page unavailable) say it was more effective than Y-27632 at suppressing profilin phosphorylation. The Discussion (page unavailable) reports that intravitreal HA-1077 improved photopic ERG responses in R6/2 mice by 40–60%. This supports improved retinal function, but not the stronger claim that it rescued the progressive retinopathy as a whole; the paper does not establish reversal of the structural retinal changes. (LLM, conf=0.87)

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Authors
Li, M., Yasumura, D., Ma, A. A. K., Matthes, M. T., Yang, H., Nielson, G., Huang, Y., Szoka, F. C., LaVail, M. M., & Diamond, M. I.
Affiliations
  • Washington University in St. Louis (US)
  • University of California, San Francisco (US)
Corresponding author
Diamond, Marc I.
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2013-02-11
Volume
8
Issue
2
Pages
e56026
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0056026
PMC
PMC3569418
OpenAlex
W2070348492
Cited by
59
References
1
Citations by year
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FWCI
2.29
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Foundation Fighting Blindness
  • Research to Prevent Blindness (EY002162)
  • Muscular Dystrophy Association
  • National Institutes of Health (EY002162, EY001919, EY006842)
  • University of California, San Francisco
  • National Eye Institute (EY 002162, P30EY002162, EY006842, R01EY001919, F32EY006842, R01EY006842, EY001919)
  • National Institute of Neurological Disorders and Stroke (R21NS076116, NS50284, R01NS050284, NS076116)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
Keywords
Huntington's disease, fasudil, ROCK inhibitor, retinal degeneration, R6/2 mouse model, profilin-1, huntingtin aggregation, intravitreal drug delivery, liposomes, electroretinogram, therapeutic time window, neurodegenerative disease treatment
MeSH terms
Huntingtin Protein, Animals, Disease Models, Animal, Electroretinography, Female, Huntington Disease, Liposomes, Nerve Tissue Proteins, Phosphorylation, Retina, Gene Expression, Retinal Cone Photoreceptor Cells, 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine, Protein Kinase Inhibitors, Profilins, Mice, rho-Associated Kinases

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