> Publications > A High-Fidelity RNA-Targeting Cas13X Downregulates Connexin43 in Macroglia: A Novel Neuroprotective Strategy for Glaucoma

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April 3, 2026 • ✎ STRIA TECH

A High-Fidelity RNA-Targeting Cas13X Downregulates Connexin43 in Macroglia: A Novel Neuroprotective Strategy for Glaucoma

Topics:

Retinal Degeneration and Inherited Retinal Disease

Retinal Ganglion Cell Pathology

The Optic Nerve, its Neurons and Diseases

Publication

Advanced Science (Weinheim) (Sep 01, 2025) A High-Fidelity RNA-Targeting Cas13X Downregulates Connexin43 in Macroglia: A Novel Neuroprotective Strategy for Glaucoma

Zhao G, Li Z, Zhao MJ, Li SY, Xia Q, Xu S, Zhang Y, Wang Y, Li F, Liu YL, Guo YH, Xu RX, Zhou H, Zhou H, Ding WW, Wang YC, Miao Y, Wang Z

DOI: 10.1002/advs.202415856 >>

In Glaucoma, ganglion cell death is mediated by activated microglia. Zhao et al found that microglia activation is aided by ATP released by macroglia, and that this release comes through connexin43 (Cx43) containing hemichannels. Using a high-fidelity RNA-targeting Cas13X (hfCas13X) system, Cx43 was selectively downregulated at the RNA level. In a chronic ocular hypertension mouse model, macroglial Cx43 knockdown reduced microglial reactivity, preserved RGC survival, and maintained optic nerve integrity. Functional analyses showed improved visual performance (measured with OptoDrum) in treated animals.

Glaucoma is a neurodegenerative disease characterized by the progressive degeneration of retinal ganglion cells (RGCs) and their axons, ultimately leading to irreversible vision loss. 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-fidelity CRISPR-Cas13 (hfCas13X) system is employed to selectively target and knock down Cx43 expression in macroglia. The findings reveal that Cx43-mediated 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-fidelity RNA editing with minimal off-target effects, represents a novel and promising therapeutic strategy for glaucoma, highlighting the potential of gene editing technologies in the management of neurodegenerative diseases.