Chen Siyu, Liu Zhiquan, Lo Chien-Hui, Wang Qing, Ning Ke, Zhang Qi, Zhao Jingyu, Shen Yingchun, Sun Yang
Department of Ophthalmology, Stanford University School of Medicine, 1651 Page Mill Road, Rm 2220, Palo Alto, CA 94304, USA.
Department of Medicine, John A. Burns School of Medicine, 651 Ilalo St, Honolulu, HI 96813, USA.
PNAS Nexus. 2025 Jun 17;4(6):pgaf168. doi: 10.1093/pnasnexus/pgaf168. eCollection 2025 Jun.
Glaucoma is a major global cause of irreversible vision loss. It is marked by elevated intraocular pressure (IOP) and the loss of retinal ganglion cells (RGC). While there are medical and surgical therapies for glaucoma aiming to reduce aqueous humor production or enhance its drainage, these treatments are often inadequate for effectively managing the disease. In this study, we developed a targeted therapy for glaucoma by knocking down two genes associated with aqueous humor production (aquaporin 1 [] and carbonic anhydrase type 2 []) using Cas13 RNA editing systems. We demonstrate that hfCas13d-mediated knockdown of and significantly lowers IOP in wild-type mice and in a corticosteroid-induced glaucoma mouse model. We show that the lowered IOP results from decreasing aqueous production without affecting the outflow facility; this treatment also significantly promotes RGC survival as compared with untreated control groups. Therefore, CRISPR-Cas-based gene editing may be an effective treatment to lower IOP for glaucomatous optic neuropathy.
青光眼是全球不可逆视力丧失的主要原因。其特征为眼压升高和视网膜神经节细胞丢失。虽然有针对青光眼的药物和手术治疗方法，旨在减少房水生成或增强其引流，但这些治疗方法往往不足以有效控制该疾病。在本研究中，我们利用Cas13 RNA编辑系统敲低两个与房水生成相关的基因（水通道蛋白1和碳酸酐酶2），开发了一种针对青光眼的靶向治疗方法。我们证明，hfCas13d介导的对这两个基因的敲低在野生型小鼠和皮质类固醇诱导的青光眼小鼠模型中均显著降低了眼压。我们表明，眼压降低是由于房水生成减少而不影响房水流出功能；与未治疗的对照组相比，这种治疗还显著促进了视网膜神经节细胞的存活。因此，基于CRISPR-Cas的基因编辑可能是降低青光眼性视神经病变眼压的有效治疗方法。
