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Gulab S. Zode, Kevin E. Bugge, Sinisa D. Grozdanic, Randy H. Kardon, Michael G. Anderson, Edwin M. Stone, Val C. Sheffield; Topical Ocular Sodium 4-phenylbutyrate Rescues Glaucoma In A Myocilin Mouse Model Of Primary Open Angle Glaucoma. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4678.
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Mutations in the myocilin gene (MYOC) are the most common known genetic cause of primary open angle glaucoma (POAG). The purpose of this study was to determine whether topical ocular sodium 4-phenylbutyrate (PBA) treatment rescues glaucoma phenotypes in a mouse model of myocilin-associated glaucoma (Tg-MYOCY437H mice).
Tg-MYOCY437H mice were treated with PBA eye drops (n=10) or vehicle (n=8) twice a day for 5 months. Long-term safety and effectiveness of topical PBA (0.2%) on glaucoma phenotypes were examined by measuring intraocular pressure (IOP) and pattern ERG (PERG), performing slit lamp evaluation of the anterior chamber, analyzing histological sections of the anterior segment, and comparing myocilin levels in the aqueous humor and in the trabecular meshwork of Tg-MYOCY437H mice. A phagocytosis assay was performed to examine PBA effect on the function of TM cells expressing mutant myocilin or treated with dexamethasone.
At 3 months of age, Tg-MYOCY437H mice exhibited elevated IOP compared to WT littermates (n=24, p<0.0001). Topical PBA did not alter IOP of WT mice. However, topical PBA significantly reduced elevated IOP in Tg-MYOCY437H mice to the level of WT mice. Topical PBA-treated Tg-MYOCY437H mice also preserved PERG amplitudes compared to vehicle-treated Tg-MYOCY437H mice. Analysis of myocilin protein in the aqueous humor and TM revealed that PBA significantly improved the secretion of myocilin and reduced myocilin accumulation as well as endoplasmic reticulum (ER) stress in the TM of Tg-MYOCY437H mice. Furthermore, PBA treatment of TM cells reversed the inhibition of phagocytosis induced by mutant myocilin or dexamethasone.
Topical ocular PBA reduces myocilin accumulation and ER stress in the TM resulting in improvement of TM cell function and effective treatment of glaucomatous phenotypes in Tg-MYOCY437H mice. These results suggest that topical ocular PBA could be a potential treatment for POAG patients with myocilin mutations.
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