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Proc Natl Acad Sci U S A. 2017 Oct 17;114(42):11199-11204. doi: 10.1073/pnas.1706193114. Epub 2017 Oct 2.

CRISPR-Cas9-based treatment of myocilin-associated glaucoma.

Author information

1
Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242.
2
North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX 76107; gulab.zode@unthsc.edu val-sheffield@uiowa.edu.
3
North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX 76107.
4
McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA 02142.
5
Stephen A. Wynn Institute for Vision Research, Department of Ophthalmology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242.
6
Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242; gulab.zode@unthsc.edu val-sheffield@uiowa.edu.

Abstract

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.

KEYWORDS:

CRISPR; genome editing; glaucoma; myocilin; trabecular meshwork

PMID:
28973933
PMCID:
PMC5651749
DOI:
10.1073/pnas.1706193114
[Indexed for MEDLINE]
Free PMC Article

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