The Development of Inherited Cortical Cataracts in a Sheep Model Is Slowed by a Macrocyclic Calpain Inhibitor

Abstract

Purpose: : To characterise the progress of cataractogenesis in sheep with an autosomal dominant gene for cataracts and use this model to evaluate novel calpain inhibitors for medical treatments of human cataract.

Methods: : Potential therapeutic compounds were screened by calpain inhibition assays, ability to protect cytoskeletal proteins from calpain proteolysis and prevention of calcium-induced opacification in cultured sheep lenses. The two most promising compounds, CAT811 and CAT505, were then formulated into an ointment and applied to the left eye of sheep twice daily for three months. There were 21 sheep with cataracts in each of the treatment groups and 20 sheep who were treated with placebo. Progress of cataracts in the sheep was determined by ophthalmologic examination and by histochemistry of the lenses.

Results: : The novel macrocyclic aldehyde, CAT811, and its alcohol analogue, CAT505, were potent calpain inhibitors in vitro. CAT811 was able to inhibit calpain proteolysis of lens cytoskeletal proteins and also reduce the opacification of cultured sheep lenses at micromolar concentrations. Topical application of CAT811 to the eyes of sheep was able to slow cataract development compared to sheep treated with placebo during a three month trial (P = 0.06).

Conclusions: : The inherited sheep cataract provides a reproducible model of cortical cataract over a time scale of several months. Our data using this model shows the potential of the macrocyclic calpain inhibitor CAT811 as a therapeutic molecule for treatment of cortical cataract.

Keywords: cataract • proteolysis • calcium