Howard Hughes Medical Institute, University of Iowa, Iowa City, Iowa, USA.
Invest Ophthalmol Vis Sci. 2012 Mar 21;53(3):1557-65. doi: 10.1167/iovs.11-8837. Print 2012 Mar.
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).
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.
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.
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.
肌球蛋白基因 (MYOC) 的突变是原发性开角型青光眼 (POAG) 最常见的已知遗传原因。本研究的目的是确定局部眼部滴眼用苯丁酸钠 (PBA) 是否可以挽救肌球蛋白相关青光眼 (Tg-MYOC(Y437H) 小鼠) 模型中的青光眼表型。
将 Tg-MYOC(Y437H) 小鼠用 PBA 眼药水（n = 10）或无菌 PBS（n = 8）每日两次治疗 5 个月。通过测量眼内压（IOP）和图形视网膜电图（PERG）、前房裂隙灯检查、分析前段组织学切片以及比较 Tg-MYOC(Y437H) 小鼠房水中和小梁网中的肌球蛋白水平，来检查局部 PBA（0.2%）对青光眼表型的长期安全性和有效性。
与野生型（WT）同窝仔相比，Tg-MYOC(Y437H) 小鼠在 3 个月大时出现眼压升高（n = 24；P < 0.0001）。局部 PBA 对 WT 小鼠的眼压没有影响。然而，它显著降低了 Tg-MYOC(Y437H) 小鼠的升高眼压，使其达到 WT 小鼠的水平。与用载体治疗的 Tg-MYOC(Y437H) 小鼠相比，用局部 PBA 治疗的 Tg-MYOC(Y437H) 小鼠还保留了 PERG 幅度。在局部 PBA 治疗的 WT 和 Tg-MYOC(Y437H) 小鼠的前房未观察到结构异常。对房水中和 TM 中的肌球蛋白分析表明，PBA 显著改善了肌球蛋白的分泌，并减少了 TM 中的肌球蛋白堆积和内质网（ER）应激。此外，局部 PBA 通过用衣霉素注射诱导 ER 应激降低了 WT 小鼠升高的眼压。
局部眼部滴眼用 PBA 降低了 Tg-MYOC(Y437H) 小鼠的青光眼表型，可能是通过减少 TM 中的肌球蛋白堆积和 ER 应激。局部眼部滴眼用 PBA 可能成为肌球蛋白突变的 POAG 患者的一种新的治疗方法。
