Purpose.: 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-MYOC Y437H mice).

Methods.: Tg-MYOC Y437H mice were treated with PBA eye drops (n= 10) or sterile PBS (n= 8) twice daily 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 histologic sections of the anterior segment, and comparing myocilin levels in the aqueous humor and trabecular meshwork of Tg-MYOC Y437H mice.

Results.: Tg-MYOC Y437H mice developed elevated IOP at 3 months of age when compared with wild-type (WT) littermates (n= 24; P< 0.0001). Topical PBA did not alter IOP in WT mice. However, it significantly reduced elevated IOP in Tg-MYOC Y437H mice to the level of WT mice. Topical PBA-treated Tg-MYOC Y437H mice also preserved PERG amplitudes compared with vehicle-treated Tg-MYOC Y437H mice. No structural abnormalities were observed in the anterior chamber of PBA-treated WT and Tg-MYOC Y437H mice. Analysis of the myocilin 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-MYOC Y437H mice. Furthermore, topical PBA reduced IOP elevated by induction of ER stress via tunicamycin injections in WT mice.

Conclusions.: Topical ocular PBA reduces glaucomatous phenotypes in Tg-MYOC Y437H mice, most likely by reducing myocilin accumulation and ER stress in the TM. Topical ocular PBA could become a novel treatment for POAG patients with myocilin mutations.