Ikeda Shin-Ichi, Sone Kohei, Takai Yoshihiro, Miyano Takayuki, Negishi Kazuno, Tsubota Kazuo, Kurihara Toshihide
Laboratory of Photobiology, Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
BMC Ophthalmol. 2025 Jul 1;25(1):383. doi: 10.1186/s12886-025-04213-6.
Myopia, characterized by excessive axial elongation of the eyeball, has become a significant global public health issue, particularly in Asia. Severe myopia increases the risk of ocular complications, including retinal degeneration and glaucoma. Recent studies have identified the role of scleral extracellular matrix remodeling and endoplasmic reticulum (ER) stress in myopia pathogenesis. Our previous study identified scleral ER stress as a critical factor in myopia development. This study aimed to investigate the therapeutic potential of 4-phenylbutyric acid (4-PBA), a chemical chaperone, in mitigating scleral ER stress and its effects on myopia progression in a mouse myopia model under masked condition.
A lens-induced myopia (LIM) mouse model was utilized to evaluate the effects of 4-PBA administered as eye drops. Mice received varying concentrations of 4-PBA or phosphate-buffered saline (PBS) as a control. Changes in refractive error and axial length were measured to assess myopia progression. In addition, further experiments were also conducted under masked conditions, where the experimenter was unaware of the treatment was being applied, for the three conditions of 2%, 0.5% 4-PBA eye drops or vehicle treatment of LIM mice.
Administration of 4-PBA at concentrations of 0.5% and higher significantly suppressed the myopic shift in refraction and axial elongation associated with myopia compared to mice in the PBS control group. In a blinded, masked experiment, 2% and 0.5% 4-PBA eye drops also suppressed the progression of myopia in a dose-dependent manner.
This study demonstrated that 4-PBA effectively mitigated myopia progression in a mouse model by targeting scleral ER stress. The dose-dependent suppression of myopic shifts and axial elongation under masked experimental condtion highlights the potential of 4-PBA as a therapeutic agent for managing myopia. These findings pave the way for further research and potential clinical applications in myopia treatment.
近视以眼球轴长过度伸长为特征，已成为一个重大的全球公共卫生问题，在亚洲尤为如此。高度近视会增加眼部并发症的风险，包括视网膜变性和青光眼。最近的研究已经确定巩膜细胞外基质重塑和内质网（ER）应激在近视发病机制中的作用。我们之前的研究确定巩膜内质网应激是近视发展的关键因素。本研究旨在探讨化学伴侣4-苯基丁酸（4-PBA）在减轻巩膜内质网应激及其对遮蔽条件下小鼠近视模型近视进展影响方面的治疗潜力。
利用晶状体诱导性近视（LIM）小鼠模型评估滴眼给予4-PBA的效果。小鼠接受不同浓度的4-PBA或作为对照的磷酸盐缓冲盐水（PBS）。测量屈光不正和眼轴长度的变化以评估近视进展。此外，还在遮蔽条件下进行了进一步实验，实验者不知道正在应用何种治疗，对LIM小鼠进行2%、0.5% 4-PBA眼药水或赋形剂治疗的三种情况。
与PBS对照组小鼠相比，给予0.5%及更高浓度的4-PBA可显著抑制与近视相关的屈光不正近视性偏移和眼轴伸长。在一项双盲、遮蔽实验中，2%和0.5% 4-PBA眼药水也以剂量依赖性方式抑制了近视进展。
本研究表明，4-PBA通过靶向巩膜内质网应激有效减轻了小鼠模型中的近视进展。在遮蔽实验条件下对近视性偏移和眼轴伸长的剂量依赖性抑制突出了4-PBA作为治疗近视药物的潜力。这些发现为近视治疗的进一步研究和潜在临床应用铺平了道路。
