Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/82999
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Type: Journal article
Title: A macrocyclic calpain inhibitor slows the development of inherited cortical cataracts in a sheep model
Author: Morton, J.
Lee, H.
McDermott, J.
Robertson, L.
Bickerstaffe, R.
Jones, M.
Coxon, J.
Abell, A.
Citation: Investigative Ophthalmology and Visual Science, 2013; 54(1):389-395
Publisher: C.V. Mosby
Issue Date: 2013
ISSN: 0146-0404
1552-5783
Organisation: Institute for Photonics & Advanced Sensing (IPAS)
Statement of
Responsibility: 
James D. Morton, Hannah Y. Y. Lee, Josh D. McDermott, Lucinda J. G. Robertson, Roy Bickerstaffe, Matthew A. Jones, James M. Coxon and Andrew D. Abell
Abstract: PURPOSE. We used sheep with an autosomal dominant gene for cortical cataract as an animal model to evaluate novel macrocyclic calpain inhibitors with potential for the medical treatment of human cataract. METHODS. The macrocyclic aldehyde, CAT811, identified previously as a calpain inhibitor that prevents calcium-induced opacification in cultured sheep lenses, was tested for its ability to protect cytoskeletal proteins from calpain proteolysis. CAT811 and its alcohol analogue, CAT505, were formulated separately into ointments, and each was applied twice daily to the right eye of sheep with early cataracts for five months. Progress of cataracts in the sheep was determined by ophthalmologic examination and comparison with a matched sample of sheep treated similarly with ointment that did not contain the active ingredient. RESULTS. The novel macrocyclic aldehyde, CAT811, was able to inhibit calpain proteolysis of lens cytoskeletal proteins at micromolar concentrations. When applied topically to the eyes of sheep, CAT811 was able to slow cataract development by 27% in the initial three months of treatment (P < 0.05). Its alcohol analogue, CAT505, was not able to slow cataractogenesis significantly. CONCLUSIONS. The inherited sheep cataract provides a reproducible model of cortical cataract over a time scale of several months. The data reported here, using this model, demonstrated the potential of the macrocyclic calpain inhibitor, CAT811, to act as a therapeutic for treatment of cortical cataract.
Keywords: Lens, Crystalline
Animals
Sheep
Cataract
Disease Models, Animal
Genetic Predisposition to Disease
Calpain
Glycoproteins
Crystallins
Cysteine Proteinase Inhibitors
Blotting, Western
Electrophoresis, Polyacrylamide Gel
Rights: © 2013 Association for Research in Vision and Ophthalmology
DOI: 10.1167/iovs.12-11088
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