Abstract

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.

Links

Publisher Full Text

Authors

Zode GS, Bugge KE, Mohan K, Grozdanic SD, Peters JC, Koehn DR, Anderson MG, Kardon RH, Stone EM, Sheffield VC

Institution

Howard Hughes Medical Institute, University of Iowa, Iowa City, Iowa, USA.

Source

Investigative ophthalmology & visual science 53:3 2012 Mar pg 1557-65

MeSH

Administration, Ophthalmic
Animals
Anti-Bacterial Agents
Aqueous Humor
Cytoskeletal Proteins
Disease Models, Animal
Eye
Eye Proteins
Female
Glaucoma, Open-Angle
Glycoproteins
Humans
Immunohistochemistry
Intraocular Pressure
Male
Mice
Mice, Transgenic
Ocular Hypertension
Ophthalmic Solutions
Phenylbutyrates
Tunicamycin

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

22328638