Final Report Summary - OCULUS (A radical approach for improved glaucoma treatment.)
Open angle glaucoma is the second most-prevalent cause of global visual handicap after cataract, currently estimated to affect upwards of 75 million people. The disease is caused by an imbalance in the production of aqueous humour (the intraocular fluid that keeps the eye inflated), and its removal through drainage channels in the anterior part of the eye. The major, so-called Conventional channel comprises a meshwork of tissue (the Trabecular Meshwork) through which aqueous drains into a narrow canal (Schlemm’s Canal) running the circumference of the Iris. A more minor, so-called Unconventional or Uveoscleral route allows some drainage of aqueous through the bundles of the Ciliary muscles. Eventually, aqueous enters the peripheral circulation through both of these routes. Maintenance of physiological IOP at 12-22mm Hg is critical to the survival of a healthy retina. If aqueous drainage is compromised, pressure builds up within the globe of the eye, damaging the optic nerve head and leading to destruction of the output neurons of the retina, the ganglion cells. Progressive loss of ganglion cells results in narrowing of visual fields and if untreated, the disease will usually result in severe visual handicap, or total blindness. First-line disease management involves the use of topically applied pressure-reducing medications (including prostaglandin analogues, carbonic anyhydrase inhibitors and ß-blockers) that, for the most part, either slow down the production of aqueous humour, or enhance its clearance through the Unconventional (Uveoscleral) outflow route, none of the currently commonly-used therapeutics primarily targeting the major, or Conventional outflow pathway (although formulations targeting the latter are now beginning to emerge). At least 6% (possibly up to 10%) of patients with open angle glaucoma (currently up to 200,000 individuals with this disease in Europe at the present time) are bilaterally sub-optimally responsive to current medications, for example, with Latanoprost (a widely used topical medication) up to half of all treated patients do not achieve >20% reduction in intraocular pressure. (In spite of the critical need to maintain daily use of such medications to preserve vision, patient compliance in the use of topical medications is also a significant problem). Surgical interventions are possible, but all are in-patient procedures and can have significant complications (e.g. the Alcon CyPass Micro Stent was withdrawn in August 2018 owing to complications). There remains therefore, an important unmet clinical need for improved methods of therapy. In this regard, we have developed and pre-clinically validated in animals displaying elevations in IOP and serving as models of open-angle glaucoma, two genetic approaches to enhancement of aqueous outflow through the Conventional (Major) drainage pathway. In one such approach, targeting the so-called “tight-junctions” joining together the endothelial cells that line Schlemm’s Canal, the Canal is made more permeable to Aqueous humour entering into it from the Trabecular Meshwork by rendering the spaces between the cells to be increased. In a second approach, the Trabecular Meshwork itself is rendered less resistant to aqueous outflow using a virally-mediated gene therapy in which a proteolytic enzyme is secreted from corneal endothelium directly into the aqueous humor, digesting components of the extracellular matrix of the Meshwork and so reducing fluid resistance. These data, together with associated IP may now assist in facilitating the development of novel methods of therapy for acute elevations in IOP and for those cases of glaucoma that are currently resistant or sub-optimally responsive to topical medications.