Panja Sudipta, Nam Mi-Hyun, Gaikwad Hanmant, Rankenberg Johanna, Nagaraj Ram H
Department of Ophthalmology, School of Medicine, Sue Anschutz-Rodgers Eye Center, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.
Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.
Front Ophthalmol (Lausanne). 2023 Oct 31;3:1274825. doi: 10.3389/fopht.2023.1274825. eCollection 2023.
Presbyopia is the progressive loss of the ability of the lens to focus on nearby objects due to its increased stiffness. It occurs in the mid-40s and continues to worsen until the mid-60s. The age-associated increase in protein cross-linking in the lens leads to protein aggregation and water insolubility, especially in the nuclear region, contributing to lens stiffness. This study reports the development of aggrelyte-2A (methyl -acetyl--(3,3-dimethylbutanoyl) cysteinate, a derivative of our previously reported aggrelyte-2) for reversing the stiffness of aged lenses. Aggrelyte-2A showed minimal toxicity in cultured mouse lens epithelial cells (up to 2000 µM) and human lens epithelial cells (up to 250 µM). Lenses from aged mice (age: 24-25 months) treated with 1 mM aggrelyte-2A for 24 h, and human lenses (age: 47-67 years) treated with 250 µM aggrelyte-2A for 48 h showed 11-14% reductions in stiffness, accompanied by an increase in acetyllysine in lens proteins, and free-thiols in the lens. Topical application of aggrelyte-2A (40 mM, 5 µl twice daily for 4 weeks) on mouse eyes significantly reduced lens stiffness. The topical application showed no toxicity to the lens, cornea, or retina, as revealed by morphological examination, H&E staining, and optical coherence tomography. These data suggest that aggrelyte-2A could be developed as a presbyopia-reversing therapeutic.
老花眼是由于晶状体硬度增加而导致其聚焦于近处物体的能力逐渐丧失的一种病症。它在40多岁时出现，并持续恶化直至60多岁。晶状体中与年龄相关的蛋白质交联增加会导致蛋白质聚集和水不溶性，尤其是在核区域，从而导致晶状体硬度增加。本研究报告了aggrelyte-2A（甲基 - 乙酰基 - (3,3 - 二甲基丁酰基) 半胱氨酸酯，我们之前报道的aggrelyte-2的衍生物）的研发情况，其可用于逆转老化晶状体的硬度。Aggrelyte-2A在培养的小鼠晶状体上皮细胞（高达2000 μM）和人晶状体上皮细胞（高达250 μM）中显示出极低的毒性。用1 mM aggrelyte-2A处理24小时的老年小鼠（年龄：24 - 25个月）晶状体，以及用250 μM aggrelyte-2A处理48小时的人晶状体（年龄：47 - 67岁），其硬度降低了11 - 14%，同时晶状体蛋白中的乙酰赖氨酸和晶状体中的游离巯基有所增加。在小鼠眼睛上局部应用aggrelyte-2A（40 mM，每天两次，每次5 μl，持续4周）可显著降低晶状体硬度。形态学检查、苏木精 - 伊红染色和光学相干断层扫描显示，局部应用对晶状体、角膜或视网膜均无毒性。这些数据表明，aggrelyte-2A可被开发成为一种逆转老花眼的治疗药物。
