Endoplasmic reticulum stress as an underlying factor in leading causes of blindness and potential therapeutic effects of 4-phenylbutyric acid: from bench to bedside

Mounting evidence has emerged showing that endoplasmic reticulum (ER) stress participates in triggering cell injuries in ocular tissues, manifested as disorders such as cataracts, age-related macular degeneration, glaucoma, and diabetic retinopathy. ER stress is a condition in which the ER is perturbed by the accumulation of unfolded and misfolded proteins. In a dynamic signaling cascade, the unfolded protein response (UPR) is triggered by three ER-transmembrane stress sensors to restore homeostasis and cell survival, however, if it fails, the cell will undergo a sustained ER stress condition which deteriorates cell function and promote cell death. Sustained ER stress is shown to contribute in a wide range of diseases including ophthalmologic disorders. Targeting ER stress by inhibitor agents might have promising therapeutic implications in treating eye disorders. The current review summarizes the results of the latest studies in support of the potential therapeutic utility of 4-phenylbutyric acid (4-PBA), an FDA approved ER stress inhibitor, in disorders leading to permanent vision loss. The therapeutic potential of 4-PBA in ophthalmic diseases is strongly supported by many experimental studies. Safety and efficacy studies of intravitreal injection of 4-PBA and other ER stress by inhibitors, are lacking.

日益增多的研究证据显示，内质网（ER）应激参与诱发眼部组织的细胞损伤，其临床表现为白内障、年龄相关性黄斑变性、青光眼及糖尿病性视网膜病变等眼部疾病。内质网应激是指内质网因未折叠蛋白与错误折叠蛋白的蓄积而发生稳态扰动的病理状态。在动态的信号级联反应中，未折叠蛋白反应（UPR）由三种内质网跨膜应激感受器激活，以恢复细胞稳态并维持细胞存活；然而，若该反应失效，细胞将进入持续性内质网应激状态，进而加剧细胞功能损伤并诱导细胞死亡。现有研究证实，持续性内质网应激与包括眼科疾病在内的多种疾病的发生发展密切相关。通过抑制剂靶向干预内质网应激，或可为眼部疾病的治疗带来颇具前景的治疗策略。本综述总结了最新研究进展，旨在佐证经美国食品药品监督管理局（FDA）批准的内质网应激抑制剂4-苯基丁酸（4-PBA）在可导致永久性视力丧失的眼部疾病中的潜在治疗价值。多项实验研究已为4-PBA在眼科疾病中的治疗潜力提供了强有力的证据支持。但目前仍缺乏针对4-PBA及其他内质网应激抑制剂的玻璃体内注射给药的安全性与有效性研究。