A Mini-Review on Gene Therapy in Glaucoma and Future Directions

Abstract

Glaucoma is a group of optic neuropathies characterized by the degeneration of retinal ganglion cells and the loss of their axons in the optic nerve. The only approved therapies for the treatment of glaucoma are topical medications and surgical procedures aimed at lowering intraocular pressure. Gene therapy involves the insertion, removal, or modification of genetic material within cells to repair or compensate for the loss of a gene's function. It describes a process or technology that enables the genetic modification of cells to produce a therapeutic effect. However, changing the genetic material alone does not extend the duration of overexpression of proteins that combat disease, nor does it facilitate the production of new proteins for this purpose. We reviewed the literature concerning the use of gene therapy in the treatment of glaucoma and explored the future directions that this innovation may offer. Three genes associated with glaucoma have been identified within these loci: myocilin/trabecular meshwork glucocorticoid response (TIGR) (GLC1A), optineurin (GLC1E), and WDR36 (GLC1G). Among these, the most extensively studied glaucoma gene is myocilin (a TM-inducible glucocorticoid response gene). Building on previous successes, researchers have begun to apply genetic therapeutic approaches to alleviate or reduce symptoms associated with ocular hypertension (OHT) and glaucoma-like optic neuropathy (GON). It is evident that several therapeutic strategies exist that modulate aqueous humor production and flow, thereby regulating intraocular pressure (IOP) and protecting retinal ganglion cells (RGCs) from apoptosis. With the emergence of gene therapy as a potentially viable approach to preserving vision, new methods for managing glaucoma may soon become available. Genomic therapy is a promising treatment option for glaucoma patients and has significant potential for widespread clinical application.

Keywords: gene mutations; gene therapy; glaucoma; intraocular pressure; retinal ganglion cells.

Figure 1

A brief history of gene therapy [8,9,10].

Figure 2

The ShH10 adeno-associated virus (AAV) serotype efficiently transduces the ciliary body epithelium following intravitreal injection. Four weeks after intravitreal administration of AAV encoding GFP driven by the CMV promoter, the ciliary body was evaluated using immunofluorescence techniques. Only the ShH10 serotype exhibited clear GFP expression in the ciliary body (A,B). Extending the evaluation to 7 weeks confirmed reduced ganglion cell loss in the treated group. Representative examples of retinal flatmount staining for Brn3a (C), along with ganglion cell quantification (D), showed that the mean Brn3a+ ganglion cell count in wild-type (WT) untreated retina was used as a reference. The quantification was based on the average of six fields per eye and expressed as mean ± SD per mm², collected from two independent experiments. Paired eyes were subsequently injected with either the ShH10-CMV-SaCas9-sgRNA B and E mix (MIX) or left untreated (UN) paired t test, n = 9 pairs. Mean ± SD is shown. Scale bars, 50 mm. ** p < 0.01 (Molecular Therapy, Jiahui Wu et al., 2020 [2]).

Figure 3

Gene therapy in animal models of glaucoma (adapted from [26,28,30]).