CRISPR-Cas9–based treatment of myocilin-associated glaucoma

Ankur Jain, Gulab Zode, Ramesh B. Kasetti, Fei A. Ran, Winston Yan, Tasneem P. Sharma, Kevin Bugge, Charles C. Searby, John H. Fingert, Feng Zhang, Abbot Clark, Val C. Sheffield

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20 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)11199-11204
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number42
DOIs
StatePublished - 17 Oct 2017

Fingerprint

Clustered Regularly Interspaced Short Palindromic Repeats
Glaucoma
Intraocular Pressure
Trabecular Meshwork
Endoplasmic Reticulum Stress
Mutation
Eye Diseases
Organ Culture Techniques
Human Genome
Therapeutics
trabecular meshwork-induced glucocorticoid response protein
Gene Editing
Primary Open Angle Glaucoma
Proteins

Keywords

  • CRISPR
  • Genome editing
  • Glaucoma
  • Myocilin
  • Trabecular meshwork

Cite this

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 ; Sheffield, Val C. / CRISPR-Cas9–based treatment of myocilin-associated glaucoma. In: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Vol. 114, No. 42. pp. 11199-11204.
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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.",
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author = "Ankur Jain and Gulab Zode and Kasetti, {Ramesh B.} and Ran, {Fei A.} and Winston Yan and Sharma, {Tasneem P.} and Kevin Bugge and Searby, {Charles C.} and Fingert, {John H.} and Feng Zhang and Abbot Clark and Sheffield, {Val C.}",
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Jain, A, Zode, G, Kasetti, RB, Ran, FA, Yan, W, Sharma, TP, Bugge, K, Searby, CC, Fingert, JH, Zhang, F, Clark, A & Sheffield, VC 2017, 'CRISPR-Cas9–based treatment of myocilin-associated glaucoma', Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 42, pp. 11199-11204. https://doi.org/10.1073/pnas.1706193114

CRISPR-Cas9–based treatment of myocilin-associated glaucoma. / 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; Sheffield, Val C.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 42, 17.10.2017, p. 11199-11204.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Jain, Ankur

AU - Zode, Gulab

AU - Kasetti, Ramesh B.

AU - Ran, Fei A.

AU - Yan, Winston

AU - Sharma, Tasneem P.

AU - Bugge, Kevin

AU - Searby, Charles C.

AU - Fingert, John H.

AU - Zhang, Feng

AU - Clark, Abbot

AU - Sheffield, Val C.

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AB - 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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