The Pathway From Genes to Gene Therapy in Glaucoma: A Review of Possibilities for Using Genes as Glaucoma Drugs

Abstract

Treatment of diseases with gene therapy is advancing rapidly. The use of gene therapy has expanded from the original concept of re-placing the mutated gene causing the disease to the use of genes to con-trol nonphysiological levels of expression or to modify pathways known to affect the disease. Genes offer numerous advantages over conventional drugs. They have longer duration of action and are more specific. Genes can be delivered to the target site by naked DNA, cells, nonviral, and viral vectors. The enormous progress of the past decade in molecular bi-ology and delivery systems has provided ways for targeting genes to the intended cell/tissue and safe, long-term vectors. The eye is an ideal organ for gene therapy. It is easily accessible and it is an immune-privileged site. Currently, there are clinical trials for diseases affecting practically every tissue of the eye, including those to restore vision in patients with Leber congenital amaurosis. However, the number of eye trials compared with those for systemic diseases is quite low (1.8%). Nevertheless, judg-ing by the vast amount of ongoing preclinical studies, it is expected that such number will increase considerably in the near future. One area of great need for eye gene therapy is glaucoma, where a long-term gene drug would eliminate daily applications and compliance issues. Here, we review the current state of gene therapy for glaucoma and the possibilities for treating the trabecular meshwork to lower intraocular pressure and the retinal ganglion cells to protect them from neurodegeneration.

Keywords: clinical trials; gene therapy; glaucoma; retinal ganglion cells; trabecular meshwork.

FiGURE 1

Number and distribution of gene therapy clinical trials that have been completed, are ongoing, or have been approved. A, Categorized by medical indications. B, Categorized by the viral vector type. C, Categorized by the different phases of the trials. D, Categorized by the countries where the trials have been submitted. Ocular gene therapy trials constitute 1.8% of the total number worldwide (34 out of 2356). Data obtained from the Journal of Gene Medicine database http://www.abedia.com/wiley/index.html updated in February 2016.

FiGURE 2

Ocular gene therapy trials.

FiGURE 3

Equal numbers of viral particles of self-complementary adeno-associated vector serotypes 1, 2, 5, 6, 8, and 9 carrying the reporter fluorescent gene GFP (scAAV.GFP) were added to HTM cells. GFP fluorescence was captured in living cells with a fluorescence microscope 3 days after infection. Serotype 2 transduces most efficiently, followed by serotypes 6 and 5. Serotypes 1, 8, and 9 are unable to deliver the reporter gene to the HTM cells.

FiGURE 4

Genes whose expression is altered by glaucomatous conditions in the trabecular meshwork. Candidate glaucoma biomarkers.

FiGURE 5

Intraocular pressure of rat eyes was measured 2 hours after the onset of the light or dark cycles. Pressure was obtained in sedated rats using a tonometer (TonoLab, Colonial Medical Supply) as described. A, Untreated right eye (control) showing normal IOP during the light cycle and elevated IOP during dark. B, Experimental left eye injected once intracamerally with scAAV2.dnRhoA showing normal IOP during both the light and dark cycles. Delivery of the transgene dnRhoA prevented elevation of IOP at night for at least 4 weeks. Adapted and reprinted with permission from JAMA Ophthalmol 2015;13:182.