January 2022

OPHTHALMOLOGY

UNCOVERING MOLECULAR MECHANISMS OF OPHTHALMIC DISEASES

By: Benjamin Thomson, PhD
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Endothelial dysfunction is a major cause of vision loss, playing a key role in such diseases as age-related macular degeneration (AMD), diabetic retinopathy and glaucoma. Using mouse genetics, animal disease models, and a combination of single-cell RNA sequencing and histological approaches, my research at Northwestern Medicine is focused on understanding the role of the vasculature in these diseases. By elucidating molecular connections between endothelial dysfunction and vision loss, my laboratory aims to identify novel therapeutic targets and translate these discoveries into patient care.​

The angiopoietin signaling pathway, composed of the angiopoietin ligands and their receptors, TIE and TEK (TIE2), is a central regulator of vascular development. Using a mouse genetics approach developed under the mentorship of Susan E. Quaggin, MD, we discovered that angiopoietin signaling is a critical regulator of Schlemm’s canal, a large vessel in the ocular anterior chamber responsible for aqueous humor homeostasis. This finding led to a multi-institution collaboration to test the contribution of this pathway to human glaucoma pathogenesis.

Through these studies, we identified novel TEK and ANGPT1 loss-of-function variants in pediatric congenital glaucoma, a severe and early-onset form of the disease. In vitro and in vivo studies confirmed that these variants disrupted protein function and were likely pathogenic. Additional TEK variants have since been discovered by our collaborators and other investigators, confirming the role of this important receptor in Schlemm’s canal development and function.

Together with Schlemm’s canal, aqueous humor outflow from the anterior chamber is mediated by the closely associated trabecular meshwork, which lies adjacent to the inner wall of the canal, providing structural support and biochemical cues guiding the canal’s development and function. Work on the angiopoietin pathway emphasized the importance of molecular cross-talk between these tissues and the potential of signaling pathways as targets for novel therapeutics that lower intraocular pressure.
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To identify additional pathways regulating this interaction, we used the newly emerging technology of single-cell RNA sequencing. We developed a transcriptomic atlas of the Schlemm’s canal endothelium and trabecular meshwork in healthy eyes as well as in the Angpt1 knockout model of primary congenital glaucoma. This approach allowed us to positively differentiate Schlemm’s canal endothelial cells from closely related lymphatic endothelial cells, and identify additional trabecular meshwork-Schlemm’s canal signaling pathways for future study.

While the link between endothelial dysfunction and intraocular pressure remains underappreciated, the importance of ocular vasculature in AMD is widely understood and is the basis for life-altering anti-VEGF therapies. The choroid and choriocapillaris form a unique vascular bed in the back of the eye that is vital for maintenance of the retinal photoreceptors and retinal pigment epithelium. In addition to the well-described link with AMD, choroidal dysfunction is tied to the poorly understood spectrum of pachychoroid diseases, including polypoidal choroidal vasculopathy (PCV), which can lead to irreversible loss of vision. Despite their clinical impact, little is known about pathogenesis or optimal treatment of PCV and other pachychoroid diseases, or why some patients with defects in the choroidal vasculature develop geographic atrophy or neovascular AMD and others develop PCV.
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To examine this process in detail, we developed a new mouse model with developmental attenuation of the choriocapillaris. These mice are born healthy, but the choriocapillaris is rapidly impinged by dilated vessels originating in the choroid, reminiscent of choroidal pachyvessels associated with pachychoroid and PCV. My current work focuses on this new animal model, leveraging this tool to gain mechanistic insights into pachychoroid biology, understand mechanisms by which choriocapillaris attenuation leads to choroidal dysfunction, and identify genes and pathways that can be targeted for future therapies.

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