Calpains as mechanistic drivers and therapeutic targets for ocular disease.

Jennifer T Vu, Elena Wang, Jolan Wu, Young Joo Sun, Gabriel Velez, Alexander G Bassuk, Soo Hyeon Lee, Vinit B Mahajan

Journal: Trends in molecular medicine 2022;28(8):644-661

PMID: 35641420

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Abstract

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.

Address: Molecular Surgery Laboratory, Byers Eye Institute, Department of Ophthalmology, Stanford University, Palo Alto, CA 94304, USA.; Department of Pediatrics, University of Iowa, Iowa City, IA, USA; Department of Neurology, University of Iowa, Iowa City, IA, USA; The Iowa Neuroscience Institute (INI), University of Iowa, Iowa City, IA, USA.; Molecular Surgery Laboratory, Byers Eye Institute, Department of Ophthalmology, Stanford University, Palo Alto, CA 94304, USA; Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA. Electronic address: [email protected].

DOI: 10.1016/j.molmed.2022.05.007

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MeSH Terms: Calcium, Calpain, Cell Death, Humans, Retina