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Val Sheffield; CRISPR-based treatment of MYOC-associated glaucoma. Invest. Ophthalmol. Vis. Sci. 201657(12):.
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© ARVO (1962-2015); The Authors (2016-present)
Presentation Description :
Glaucoma is a leading cause of irreversible blindness with elevated intraocular pressure (IOP) being the most important risk factor. Mutations in myocilin, coded for by the MYOC gene, lead to misfolding and endoplasmic reticulum (ER) stress in the trabecular meshwork (TM), the tissue that maintains aqueous humor outflow and regulates IOP. ER stress and/or death of the TM lead to ocular hypertension and glaucoma. Since the phenotype seems to result from the mutant misfolded protein rather than resulting from loss of myocilin function or haplo-insufficiency, we hypothesized that ER stress and glaucoma can be relieved and prevented by targeting the MYOC gene using CRISPR-Cas9 genome editing technology in vitro (human and mouse cells) and in vivo (mouse models). Mouse TM cells and human primary TM cells, as well as hMYOCY437H transgenic and DEX-induced ocular hypertensive mice were treated with Ad5-CRISPR-Cas9 virus with MYOC and control guide RNAs. Treated and control cells and mice were evaluated for ER stress and glaucoma phenotypes. Treatment with CRISPR-Cas9 with gRNAs targeting exon 1 of the MYOC gene reduces levels of MYOC and ER stress in MYOC mutant cells. We will also report on the effects of CRISPR-Cas9 treatment of mouse models of MYOC glaucoma and DEX-induced ocular hypertension. This proof of principle study indicates that genome editing targeting the MYOC gene can relieve ER stress in TM cells and in transgenic hMYOCY437H and DEX-induced ocular hypertension mouse models.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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