Dynamic Variable Aqueous Humor Outflow and Glaucoma Therapies in the Human Eye

University Of California, San Diego, La Jolla CA

Investigators

Linked publications, trials & patents

Abstract

Glaucoma is a leading cause of blindness, worldwide. The only proven glaucoma treatment is intraocular pressure (IOP) reduction. Elevated IOP is caused by increased aqueous humor outflow (AHO) resistance at the trabecular meshwork (TM) of the trabecular AHO pathways. Medications can be used to lower AHO resistance through these pathways, but patients can be medically non-responsive for unclear reasons. Trabecular ablation was developed as a safe and logical treatment, but IOP-lowering efficacy is limited in large, well-controlled clinical trials. Thus, current glaucoma therapies are not effective enough, and there are insufficient tools to fully assess AHO anatomy and physiology across the entire eye to understand why. Aqueous angiography (AA) is an AHO visualization method that has shown segmental AHO over the entire eye with high-flow (HF) and low-flow (LF) regions. LF regions have been linked to glaucoma treatment success. However, while AA provides gold-standard AHO information, it is an invasive method with risks. Thus, we must derive a biologically-focused anterior segment AHO structure/function relationship and re-frame segmental AHO assessment as a non-invasive structural test to fill this gap. To do this, specialized optical coherence tomography (OCT) approaches must be taken to overcome the complex, large, and three-dimensional AHO pathway anatomy. Thus, our central hypothesis is that improved understanding of the ocular structures that determine segmental AHO (particularly LF regions) in normal and diseased eyes can improve current and lead to new glaucoma therapies. The objectives are to understand the structural determinants and identify biomarkers of segmental AHO, use this knowledge to test glaucoma treatments, and create new tools to better evaluate AHO pathways in humans. In Aim 1, we will use AA, OCT, and lipid emulsion (LE) OCT-angiography (OCTA) in ex-vivo human eyes to define the AHO pathway structures that define segmental AHO LF and HF subtypes. These areas will then be tested using trabecular ablation to identify the best locations for improving outflow facility and reducing IOP. In Aim 2, we will use OCT and OCTA in wild-type and glaucoma mice with high IOP to define AHO pathway structures that define segmental AHO in a pathophysiological state. These areas will then be studied using glaucoma IOP- lowering drugs. In Aim 3, we will develop a new robotic anterior segment OCT (AS-OCT) tailored to human AHO anatomy with high spatial resolution, optimal spectral range to reach the desired depth, and robust safety features. Robotic control improves speed, feasibility, and reliability. Early-stage clinical performance and repeatability testing will be performed in healthy volunteers and glaucoma patients using body-position-induced IOP alteration to iteratively optimize the operation protocol. This proposal brings together the optimal team. Dr. Zhang is a bioengineer who has successfully designed many custom OCT systems, including for the anterior segment, to improve ocular anatomical and physiological assessment. Dr. Huang is a clinician-scientist who developed AA, has published on clinical AS-OCT, and cares for glaucoma patients.