CRISPR-Cas9–based treatment of myocilin-associated glaucoma

• Published in: Proceedings of the National Academy of Sciences - PNAS 2017-10, Vol.114 (42), p.11199-11204
• Main Authors: Jain, Ankur, Zode, Gulab, Kasetti, Ramesh B., Ran, Fei A., Yan, Winston, Sharma, Tasneem P., Bugge, Kevin, Searby, Charles C., Fingert, John H., Zhang, Feng, Clark, Abbot F., Sheffield, Val C.
• Format: Article
• Language: English
• Subjects: Animals; Biological Sciences; Cell culture; Cell Line; CRISPR; CRISPR-Cas Systems; Cytoskeletal Proteins - genetics; Damage prevention; Editing; Endoplasmic reticulum; Eye Proteins - genetics; Feasibility studies; Gene Editing; Genetic Therapy - methods; Genomes; Glaucoma; Glaucoma, Open-Angle - genetics; Glaucoma, Open-Angle - therapy; Glycoproteins - genetics; Humans; In Vitro Techniques; Intraocular pressure; Mice; Mutation; Organ culture; Protein folding; Risk factors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1706193114

Primary open-angle glaucoma (POAG) is a leading cause of irreversible vision loss worldwide, with elevated intraocular pressure (IOP) a major risk factor. Myocilin (MYOC) dominant gain-of-function mutations have been reported in ∼4% of POAG cases. MYOC mutations result in protein misfolding, leading to endoplasmic reticulum (ER) stress in the trabecular meshwork (TM), the tissue that regulates IOP. We use CRISPR-Cas9–mediated genome editing in cultured human TM cells and in a MYOC mouse model of POAG to knock down expression of mutant MYOC, resulting in relief of ER stress. In vivo genome editing results in lower IOP and prevents further glaucomatous damage. Importantly, using an ex vivo human organ culture system, we demonstrate the feasibility of human genome editing in the eye for this important disease.