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.