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Gulab S. Zode, Darryl Y. Nishimura, Qiong Ding, Charles C. Searby, Kabhilan Mohan, Sinisa D. Grozdanic, Edvin M. Stone, Val C. Sheffield, Markus H. Kuehn; A Chemical Chaperone Rescues Glaucoma By Reducing ER Stress In A Novel Murine Model Of Primary Open Angle Glaucoma. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5917.
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© ARVO (1962-2015); The Authors (2016-present)
Myocilin (MYOC) mutations are the most common single cause of primary open angle glaucoma (POAG). However, mechanisms underlying MYOC-associated glaucoma are not fully understood, and a mouse genetic model that closely mimics human POAG has not been developed. The aims of this study were to a) develop a mouse POAG model b) utilize this model to investigate underlying pathogenic mechanisms, and c) evaluate therapies for treatment of MYOC-associated glaucoma.
We generated transgenic mice (Tg-MYOC-Y437H) carrying human mutant MYOC with a tyrosine to histidine substitution at codon 437 under the control of the CMV promoter. Glaucoma phenotypes were examined by measuring intraocular pressure (IOP), retinal ganglion cell (RGC) death, and optic nerve degeneration (44 WT, 80 Tg-MYOC-Y437H mice). Western blotting and immuno-staining were used to examine myocilin expression, as well as markers of endoplasmic reticulum (ER) stress in the trabecular meshwork (TM) of Tg-MYOC-Y437H mice. The chemical chaperone, phenyl butyric acid (PBA), was given orally to Tg-MYOC-Y437H mice.
Tg-MYOC-Y437H mice displayed ocular manifestations of glaucoma including elevated IOP (7mm Hg increase vs WT; p<0.0001) at 3 months of age, progressive structural and functional loss of RGCs (40% loss by 12months; p<0.001), and optic nerve degeneration (45% reduction in axons count by 12months; p<0.001). Mutant MYOC accumulated in the ER, activated ER stress, and preceded TM cell death in vitro and in vivo. Mitigation of ER stress by oral administration of PBA rescued glaucoma phenotypes including normalization of elevated IOP, prevention of structural and functional loss of RGCs, as well as axonal degeneration in treated (n=14) compared to untreated Tg-MYOC-Y437H mice (n=10).
ER stress is critical to the pathogenesis of MYOC-associated glaucoma and is a potential treatment target for POAG with chemical chaperones based on studies in a novel mouse model of POAG.
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