Progress in Gene Therapy to Prevent Retinal Ganglion Cell Loss in Glaucoma and Leber’s Hereditary Optic Neuropathy

Abstract

The eye is at the forefront of the application of gene therapy techniques to medicine. In the United States, a gene therapy treatment for Leber's congenital amaurosis, a rare inherited retinal disease, recently became the first gene therapy to be approved by the FDA for the treatment of disease caused by mutations in a specific gene. Phase III clinical trials of gene therapy for other single-gene defect diseases of the retina and optic nerve are also currently underway. However, for optic nerve diseases not caused by single-gene defects, gene therapy strategies are likely to focus on slowing or preventing neuronal death through the expression of neuroprotective agents. In addition to these strategies, there has also been recent interest in the potential use of precise genome editing techniques to treat ocular disease. This review focuses on recent developments in gene therapy techniques for the treatment of glaucoma and Leber's hereditary optic neuropathy (LHON). We discuss recent successes in clinical trials for the treatment of LHON using gene supplementation therapy, promising neuroprotective strategies that have been employed in animal models of glaucoma and the potential use of genome editing techniques in treating optic nerve disease.

Nucleic acid delivery to differentiated retinal pigment epithelial cells using cell-penetrating peptide as a carrier

“…However, the efficiency and safety of the cargo (DNA or RNA) and its delivery to the back of the eye remain a limiting factor [2][3][4]. Although viral vectors can deliver genes efficiently, there are problems related to their safety and large-scale production [5].…”

Current Medical Therapy and Future Trends in the Management of Glaucoma Treatment

“…Gene therapy aims to correct a specific, well defined genetic defect or deliver protective factors using different pathways to stimulate survival and regeneration of retinal ganglion cells. The most promising vector systems for successful gene delivery in the eye are recombinant adenoassociated viral vectors (AAVs), which lead to long and sustained levels of gene expression within a select target cell [ 128 ]. Genetic approach is still in preclinical phase for glaucoma.…”

“…The etiopathogenesis of adult-onset glaucoma is not clear and includes various genetic, environmental, and individual risk factors. For these reasons, gene therapy strategies are based on enhancing retinal ganglion cell survival or inhibiting cell death pathways [ 128 ]. Supplementation of brain-derived neurotrophic factors showed transient neuroprotective effect due to BDNF receptor (TrKB) downregulation [ 132 ].…”

Neuroprotection in Glaucoma: Towards Clinical Trials and Precision Medicine

“…54 It is conceivable that combining two or more transgenes coding for proteins targeting multiple pathways related to glaucoma pathogenesis could provide an effective approach to deliver targeted, sustained and individualised treatment to maximise efficacy. We have also discussed the use of CRISPR/Cas9 as a gene-editing tool for glaucoma elsewhere 97 and other gene and post-translation modification approaches to modify ocular disease have been extensively reviewed. 98 Valuable lessons can be learned from the oncology community, where breast cancer molecular and genetic phenotyping are now used widely in clinical practice to tailor treatment to individuals.…”