title: A macrocyclic calpain inhibitor slows the development of inherited cortical cataracts in a sheep model.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Wine, Food and Molecular Biosciences, Faculty of Agriculture and Life Sciences, Lincoln University, Canterbury, New Zealand. mortonj@lincoln.ac.nz
authors.forename: James D
authors.initials: JD
authors.lastname: Morton
authors.forename: Hannah Y Y
authors.initials: HY
authors.lastname: Lee
authors.forename: Josh D
authors.initials: JD
authors.lastname: McDermott
authors.forename: Lucinda J G
authors.initials: LJ
authors.lastname: Robertson
authors.forename: Roy
authors.initials: R
authors.lastname: Bickerstaffe
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Jones
authors.forename: James M
authors.initials: JM
authors.lastname: Coxon
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Abell
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002154:Calpain / Q000037:antagonists & inhibitors; D002386:Cataract / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D003459:Crystallins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D004591:Electrophoresis, Polyacrylamide Gel; D020022:Genetic Predisposition to Disease; D006023:Glycoproteins / Q000494:pharmacology*; D007908:Lens, Crystalline / Q000187:drug effects / Q000378:metabolism*; D012756:Sheep
chemical_list: D003459:Crystallins; D015853:Cysteine Proteinase Inhibitors; D006023:Glycoproteins; C039304:calpain inhibitors; D002154:Calpain