Journal article
CRISPR-Cas9-based treatment of myocilin-associated glaucoma
Proceedings of the National Academy of Sciences - PNAS, Vol.114(42), pp.11199-11204
10/17/2017
DOI: 10.1073/pnas.1706193114
PMCID: PMC5651749
PMID: 28973933
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 ( ) dominant gain-of-function mutations have been reported in ∼4% of POAG cases. 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.
Details
- Title: Subtitle
- CRISPR-Cas9-based treatment of myocilin-associated glaucoma
- Creators
- Ankur Jain - Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242Gulab Zode - North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX 76107; gulab.zode@unthsc.edu val-sheffield@uiowa.eduRamesh B Kasetti - North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX 76107Fei A Ran - McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA 02142Winston Yan - Massachusetts Institute of TechnologyTasneem P Sharma - Stephen A. Wynn Institute for Vision Research, Department of Ophthalmology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242Kevin Bugge - Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242Charles C Searby - Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242John H Fingert - Stephen A. Wynn Institute for Vision Research, Department of Ophthalmology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242Feng Zhang - McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA 02142Abbot F Clark - North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX 76107Val C Sheffield - Stephen A. Wynn Institute for Vision Research, Department of Ophthalmology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.114(42), pp.11199-11204
- DOI
- 10.1073/pnas.1706193114
- PMID
- 28973933
- PMCID
- PMC5651749
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- United States
- Grant note
- P30 EY025580 / NEI NIH HHS R00 EY022077 / NEI NIH HHS R01 EY026177 / NEI NIH HHS Howard Hughes Medical Institute R01 EY024259 / NEI NIH HHS
- Language
- English
- Date published
- 10/17/2017
- Academic Unit
- Stead Family Department of Pediatrics; The University of Iowa Institute for Vision Research; Iowa Neuroscience Institute; Medical Genetics and Genomics; Ophthalmology and Visual Sciences
- Record Identifier
- 9983979963802771
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