CRISPR-Cas9–based treatment of myocilin-associated glaucoma

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...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 114; no. 42; pp. 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 Journal Article
LanguageEnglish
Published United States National Academy of Sciences 17.10.2017
SeriesFrom the Cover
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
myocilin
CRISPR
genome editing
glaucoma
trabecular meshwork
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Summary: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.
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Author contributions: A.J., G.Z., F.Z., A.F.C., and V.C.S. designed research; A.J., G.Z., R.B.K., T.P.S., K.B., and C.C.S. performed research; F.A.R., W.Y., T.P.S., J.H.F., F.Z., and A.F.C. contributed new reagents/analytic tools; A.J., G.Z., A.F.C., and V.C.S. analyzed data; and A.J., G.Z., A.F.C., and V.C.S. wrote the paper.
Edited by Donald J. Zack, Johns Hopkins University, Baltimore, MD, and accepted by Editorial Board Member Jeremy Nathans August 25, 2017 (received for review April 22, 2017)
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1706193114