Myocilin (MYOC) (MYOC)

Myocilin (MYOC) is a secreted glycoprotein primarily expressed in the trabecular meshwork (TM) of the eye, where it is involved in the regulation of intraocular pressure (IOP) (UniProt P35030). Mutations in the MYOC gene, such as the common P370L variant, cause the protein to misfold and accumulate in the endoplasmic reticulum (ER), leading to chronic ER stress and TM cell death (Zode et al., 2011, Investigative Ophthalmology & Visual Science). This pathological process impairs aqueous humor drainage, resulting in elevated IOP and the development of primary open-angle glaucoma (POAG) (NCBI Gene ID: 4653). As a therapeutic target, mutated MYOC is being addressed through gene-editing technologies like CRISPR/Cas9 to disrupt the mutant allele and reduce toxic protein levels (Jain et al., 2017, Molecular Therapy). Additionally, chemical chaperones like 4-phenylbutyrate are being explored to assist in the proper folding and secretion of the protein to alleviate ER stress (PubMed: 21245395). While the loss of myocilin does not appear to cause adverse phenotypes in mice, ensuring the safety and specificity of genetic interventions remains a primary challenge in clinical development. The target is unique because the disease is caused by a toxic gain-of-function rather than a loss of function, making knockdown strategies particularly viable.

Other names

Trabecular meshwork-induced glucocorticoid response proteinTIGRGLC1AJOAGGPOA

Reduction of mutant protein accumulation through gene editing, gene silencing, or chemical chaperone-mediated protein folding stabilization.