Calpains as mechanistic drivers and therapeutic targets for ocular disease.

Ophthalmic neurodegenerative diseases encompass a wide array of molecular pathologies unified by calpain dysregulation. Calpains are calcium-dependent proteases that perpetuate cellular death and inflammation when hyperactivated. Calpain inhibition trials in other organs have faced pharmacological challenges, but the eye offers many advantages for the development and testing of targeted molecular therapeutics, including small molecules, peptides, engineered proteins, drug implants, and gene-based therapies. This review highlights structural mechanisms underlying calpain activation, distinct cellular expression patterns, and in vivo models that link calpain hyperactivity to human retinal and developmental disease. Optimizing therapeutic approaches for calpain-mediated eye diseases can help accelerate clinically feasible strategies for treating calpain dysregulation in other diseased tissues. The eye is an attractive model organ to study molecular therapeutic interventions for neurodegenerative diseases caused by calpain hyperactivity. Calcium-mediated calpain hyperactivity is a central molecular mediator of several ocular diseases, leading to cell death, inflammation, and neovascularization. Calpainopathies caused by Mendelian defects in CAPN5 and CAPN15 result in eye-specific diseases, including neovascular inflammatory vitreoretinopathy and ocular developmental anomalies, respectively. Novel structure–function studies and translational models of eye disease have shed light on mechanisms underlying calpain hyperactivity. Small-molecule calpain inhibitors, protein, peptide, and gene-based therapies are promising avenues of treatment for calpain-mediated ocular diseases, especially given the eye's accessibility to targeted molecular therapy. [ABSTRACT FROM AUTHOR]