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Scott Ellis, Katie Binley, Vicky Scripps, Sharifah Iqball, Stuart Naylor, Kyriacos Mitrophanous; Glaucoma-GT, a novel gene therapy treatment for primary open-angle glaucoma. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2741.
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Glaucoma is the second leading cause of blindness worldwide, affecting around 70 million people, over 2.5 million people in the USA alone. It is characterized by irreversible degeneration of the optic nerve, usually associated with an elevated intraocular pressure (IOP). Prostenoid analogues such as Latanoprost are a first-line treatment for glaucoma due to their high level of efficacy and low risk of side-effects, but fail to halt disease progression in many patients due to non-adherence, which can be >50%. Surgery is often required, which is expensive and only partially effective. There is therefore a real medical need for a novel drug that overcomes this issue of poor compliance. Initial proof-of-concept for this approach has been demonstrated (Barraza et al, 2010), and we are now moving this into a translational gene therapy platform for clinical evaluation. Glaucoma-GT is a gene therapy product aimed at lowering IOP via the prostenoid pathway: a single transcorneal administration leads to the expression of human cyclooxygenase-2 (COX-2) and prostaglandin F (FP) receptor in the front of the eye. COX-2 is a rate-limiting enzyme in the biosynthesis of prostaglandins, and both COX-2 and the FP receptor are down-regulated in glaucomatous eyes. Expression of both genes increases both prostaglandin 2α (PGF2α) biosynthesis and signaling, increasing aqueous outflow and reducing longterm IOP.
Gene transfer following transcorneal administration of EIAV-GFP vector was characterised in animal models. Various vector genome configurations were assessed for the production of PGF2α and activation of the FP receptor in in vitro assays. Further preclinical studies are currently ongoing and data from these will be presented.
Transcorneal injection of EIAV vector led to the transduction of cells of the trabecular meshwork and corneal endothelium in vivo. Different configurations of expression cassette gave a broad range of PGF2α and FP activation, with CMV-COX-2-IRES-FP having the highest activity.
We have demonstrated significant gene transfer following transcorneal administration of EIAV-GFP vector in animal models, and have optimised the therapeutic expression cassette to produce high levels of prostaglandin 2α and enhanced FP activation in in vitro studies. These vector configurations will be assessed for IOP lowering in a relevant animal model.
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