Could increasing the pores in the eye’s drainage system be a potential treatment for glaucoma?
- Type of funding: PhD Studentship
- Grant Holder: Dr Darryl Overby
- Institute: Imperial College London
- Region: London
- Start date: October 2012
- End Date: September 2015
- Eye Category: Glaucoma
Glaucoma is a leading cause of irreversible blindness. The only treatment so far is to significantly lower pressure in the eye (intraocular pressure) over a long period of time – something that’s hard to do.
Intraocular pressure is determined by a balance between the rate at which the eye makes and drains the clear watery fluid that fills the front of the eye (aqueous humour). Raised resistance to the outflow of aqueous humour is the root cause of high eye pressure (ocular hypertension) linked to glaucoma. But we don’t have a good understanding of the mechanics behind increased outflow resistance.
The front of the eye contains a channel called Schlemm’s canal that collects aqueous humour from the eye and delivers it into the bloodstream through pores along the channel. But in glaucoma, the number of pores in Schlemm’s canal is lower than usual and this may be what leads to poor drainage, raised resistance to outflow and increased eye pressure.
Dr Overby’s group has developed a lab dish model that mimics the reduced pores found in glaucoma. In this project they’re aiming to develop a therapy that stimulates the natural process that forms pores to increase their number in Schlemm’s canal tissue. Their model is first being used as a platform to screen for potential substances that encourage pores to form, and any they find are going through extra testing to assess their effect.This is a proof-of-concept study that aims to find out how well therapy to produce more pores can work for treating glaucoma.
Triggering pore formation in Schlemm’s canal endothelial cells as a potential treatment for glaucoma
Schlemm’s canal endothelium (SCE) is a nearly continuous endothelial barrier that resides at the primary site of outflow resistance generation in the conventional outflow pathway. SCE contains micron-sized pores that provide a pathway for aqueous humour flow across an otherwise relatively impermeable endothelium, and SCE pore density is reduced in glaucoma. The goal of this project is to develop a molecular approach to enhance the natural pore-forming mechanisms of SCE cells as a means to reduce outflow resistance and more successfully lower IOP.
The team has developed the first in vitro assay for pore formation in SCE cells, where SCE cells are seeded on filter membranes and perfused in the basal-to-apical direction to mimic the direction of aqueous humour flow across SCE in vivo. Using this assay they have established that pore formation is mechanosensitive, with increasing pore density as a function of perfusion pressure, and that pore formation is impaired in human SCE cells cultured from glaucomatous eyes.They now exploit this assay to screen for compounds that promote pore formation in human SCE and porcine anterior aqueous plexus cells, focussing on compounds already shown to induce pore formation in vascular endothelial cells. Compounds found to induce pore formation in SCE cells in vitro are being advanced to perfusion studies to assess their effect on outflow resistance in enucleated porcine and murine eyes. Results from this study will identify candidate therapeutic molecules and establish proof-of-principle that targeting pore formation is a promising therapeutic strategy to more successfully lower IOP in glaucoma.
Research updateDr Overby’s laboratory has developed a better system for fluid flow through tissue (perfusion) and experiments that previously took a month can now be done in under a week with greater accuracy and confidence.
PublicationsSherwood JM, Reina-Torres E, Bertrand JA, Rowe B, Overby DR. Measurement of Outflow Facility Using iPerfusion. PLoS ONE. 2016 Mar 7;11(3):e0150694.