MicroRNA based therapeutics to treat ocular fibrosis in glaucoma.

Overview

The eye maintains a constant pressure by continuously producing fluid (called aqueous humour) while an equal amount of the fluid drains out of the eye through what’s known as the trabecular meshwork. A protein called TGFβ is increased in the aqueous humour of glaucoma patients and in the most common type of glaucoma, known as ‘primary open-angle glaucoma’, the trabecular meshwork becomes blocked slowly over time. As pressure in the eye mounts the optic nerve becomes damaged, leading to serious, irreversible sight loss if left untreated. Lowering IOP is the only clinical therapy currently available to treat glaucoma.

None of the current pharmacological agents target the effects of TGFβ which damages the trabecular meshwork producing raised eye pressure (intraocular pressure: IOP). The disease in the trabecular meshwork is, therefore, unchecked, and so the IOP continues to rise requiring further medical or surgical interventions. With surgery, the aqueous humour is directed under the lining of the eye (conjunctiva) but as it still contains TGFβ there is a scarring response which can result in failure of the operation to control IOP and stabilise the disease. This scarring response under the conjunctival involves cells called Tenon fibroblasts. Surgeons use potent and toxic anti-cancer drugs to prevent scarring and surgical failure which have significant sight-threatening side effects.

The researhcers pilot work has identified small, naturally occurring regulatory genes called microRNAs which target TGFβ and that can be manipulated therapeutically: GlaucoMirs.

The aim of this study is to develop miRNA-based therapeutics (GlaucoMirs) to treat TGFβ induced fibrosis in the trabecular meshwork and in Tenon fibroblasts to improve the treatment of glaucoma medically and surgically. This project will provide significant insight into the molecular changes that cause glaucoma in the trabecular meshwork. The data from this project will allow the researchers to develop a new class of disease-modifying therapeutics targeting TGFβ in glaucoma based on miRNA biology.

The implications of this work can transcend glaucoma and miRNA-based therapeutic approaches could be directed to other TGFβ driven ocular scarring: corneal disease and retinal scarring in diabetic eye disease, AMD and following retinal detachment surgery.