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

doi:10.1016/j.molmed.2022.05.007

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Calpains as mechanistic drivers and therapeutic targets for ocular disease

Journal article

Peer reviewed

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 and Vinit B. Mahajan

Trends in molecular medicine, Vol.28(8), pp.644-661

05/28/2022

DOI: 10.1016/j.molmed.2022.05.007

PMCID: PMC9345745

PMID: 35641420

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https://www.ncbi.nlm.nih.gov/pmc/articles/9345745View

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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. 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.

Blindness

calcium dysregulation

calpain

retina

therapeutics

Details

Title: Subtitle: Calpains as mechanistic drivers and therapeutic targets for ocular disease
Creators: Jennifer T. Vu - Stanford University
Elena Wang - Stanford University
Jolan Wu - Stanford University
Young Joo Sun - Stanford University
Gabriel Velez - Stanford University
Alexander G. Bassuk - University of Iowa
Soo Hyeon Lee - Stanford University
Vinit B. Mahajan - Stanford University
Resource Type: Journal article
Publication Details: Trends in molecular medicine, Vol.28(8), pp.644-661
DOI: 10.1016/j.molmed.2022.05.007
PMID: 35641420
PMCID: PMC9345745
NLM abbreviation: Trends Mol Med
ISSN: 1471-4914
eISSN: 1471-499X
Publisher: Elsevier Ltd
Language: English
Date published: 05/28/2022
Academic Unit: Neurology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Biochemistry and Molecular Biology; Neurology (Pediatrics)
Record Identifier: 9984262859402771

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