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Elevated intraocular pressure (IOP) is one of the significant risk factors in glaucoma; however, neurodegeneration continues even after effective IOP management, underscoring the need for neuroprotective therapies. This study investigates the role of connexin43 (Cx43), which is extensively expressed in retinal macroglia, in regulating microglial activation and optic nerve degeneration in glaucoma. A high\u2010fidelity CRISPR\u2010Cas13 (hfCas13X) system is employed to selectively target and knock down Cx43 expression in macroglia. The findings reveal that Cx43\u2010mediated ATP release through hemichannels exacerbates microglial activation and neuroinflammation, thereby contributing to RGC loss. Notably, in a mouse model of chronic ocular hypertension (COH) glaucoma, knocking down Cx43 in macroglia using the hfCas13X system significantly promoted the survival of RGCs and the integrity of the optic nerve, and improved visual function. The hfCas13X system, which offers high\u2010fidelity RNA editing with minimal off\u2010target effects, represents a novel and promising therapeutic strategy for glaucoma, highlighting the potential of gene editing technologies in the management of neurodegenerative diseases.<\/jats:p>","DOI":"10.1002\/advs.202415856","type":"journal-article","created":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T08:53:18Z","timestamp":1750323198000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A High\u2010Fidelity RNA\u2010Targeting Cas13X Downregulates Connexin43 in Macroglia: A Novel Neuroprotective Strategy for Glaucoma"],"prefix":"10.1002","volume":"12","author":[{"given":"Guoli","family":"Zhao","sequence":"first","affiliation":[{"name":"State Key Laboratory of Brain Function and Disorders and MOE Frontiers Center for Brain Science Institutes of Brain Science Fudan University  Shanghai 200032 China"},{"name":"Eye 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