CRISPR-Based Disruption of MYOC Gene Rescues Disease Phenotypes in Mouse Model of Glaucoma

Primary open-angle glaucoma (POAG) is the most prevalent form of glaucoma and is responsible for approx. 12 % of all cases of blindness worldwide. The leading genetic cause of POAG is mutations in the myocilin-encoding gene MYOC. Myocilin is highly expressed in the trabecular meshwork (TM), which plays an important role in the regulation of intraocular pressure. Mutations in MYOC result in a gain-of-function phenotype whereby mutant myocilin accumulates in the endoplasmic reticulum (ER) leading to ER stress and cell death within the TM.

Given its prominent role in the pathobiology of POAG, myocilin has been pursued as a therapeutic target for the disease. In an article published in PNAS in 2017, researchers in the US demonstrated the possibility of disrupting MYOC using an adenovirus 5 (Ad5)-mediated CRISPR-Cas9 editing strategy. Since Ad5 is not considered to be suitable for clinical use, the same team, based at University of North Texas, University of California, and University of Iowa, recently explored the efficacy of adeno-associated viruses (AAVs) and lentiviruses (LVs) to target myocilin in the TM.

The team compared a range of GFP-expressing AAV and LV vectors following intravitreal and intracameral injections. They found that a single intravitreal injection of LV particles expressing Cas9 and a guide RNA that targets MYOC led to a significant reduction in intraocular pressure and a decrease in myocilin accumulation in the TM in a mouse model of POAG. Their findings suggest that CRISPR-based disruption of MYOC has potential as a novel therapeutic strategy for POAG.

The study was published last week in Science Reports.

doi: 10.1038/s41598-024-57286-6.