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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Veröffentlicht in:	Proceedings of the National Academy of Sciences - PNAS 2017-10, Vol.114 (42), p.11199-11204
Hauptverfasser:	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.
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Sprache:	eng
Schlagworte:	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
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container_title	Proceedings of the National Academy of Sciences - PNAS
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creator	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.
description	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.
doi_str_mv	10.1073/pnas.1706193114
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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. 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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
title	CRISPR-Cas9–based treatment of myocilin-associated glaucoma
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