Current Research

Structure and Function of the Distal Outflow Tract

Project Narrative

Although primary open angle glaucoma (POAG) is a leading cause of irreversible blindness from elevated fluid pressure within the eye, half the resistance to drainage of this fluid remains unexplained. Prior research focused on improving the function of a strainer tissue at the intake of the eye’s drainage system, but even complete removal through surgery fails to reduce resistance to drainage sufficiently. The proposed translational research aims to enable reduction of such resistance and expand and regenerate the drainage vessels of the outflow system, using new tools developed by the PI and delivering molecules recently discovered to play an essential role in the developing outflow system.

Project Summary

Glaucoma is a leading cause of blindness with rising prevalence, that exacts costs of $2.5 B in the US alone each year. Up to 3% of the population over the age of 50 have glaucoma and 13% by the age of 80, depending on ethnicity. There is an unmet need for better therapies because the cause of the destructive elevated intraocular pressure (IOP) in glaucoma is only partially understood. The trabecular meshwork (TM) that guards the intake of the eye's drainage system intake has long been considered the principal cause of decreased outflow in primary open angle glaucoma. However, our TM ablation studies in over a thousand patients strongly suggest that at least 50% of outflow resistance resides further downstream, distal to both TM and Schlemm’s canal (SC). The overarching goals are to identify the mechanisms of post-trabecular meshwork outflow resistance in glaucoma and to develop new therapeutic strategies for improving outflow. The distal outflow resistance has to reside either in the collector channels (CC), the intrascleral plexus (ISP) or aqueous veins (AV), collectively known as the distal outflow tract (OT). Micro-computed tomography analysis of collector channels in glaucomatous eyes revealed fewer functional outflow vessels than in healthy eyes. Insights into their origin and function point toward an as-yet unexploited similarity to blood and lymphatic vessels. Strikingly, key mediators of vasculogenesis and vasodilation are now implicated in having a role in outflow, yet none have been explored therapeutically.

We generated new tools to accomplish this goal, including a translationally relevant porcine anterior segment perfusion system, a method to quantify site-specific outflow, a full-thickness, 3D confocal microscopy of the OT, and measurement of aqueous vasodilation. Using these, we discovered that OT dilation increases the outflow facility, even after TM ablation. Here, we aim to define factors of post-TM outflow regulation to enable new treatment strategies. Aim 1: determine the effects of vasodilators ("X") and ("Y") on OT structures and flow regulation. Aim 2: determine if angiogenic development can be induced by ("X") and ("Y") delivered as transgenes to generate new OT elements. Aim 3: assess whether ("Z") can initiate OT expansion by stimulating a subclass of angiogenesis. The results will yield the first analysis of the relationship between the distal OT structures and outflow function. They will provide insight into how angiogenic and dilation pathways are regulated through transcriptome analysis. This research will enable new tools to manipulate OT structure and function in porcine and human eyes, which will improve outflow, lower IOP, and improve clinical management and outcomes in glaucoma patients.