Retinal Physician Supplement

THE TIE2 PATHWAY 2017

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PARTICIPANTS Peter K. Kaiser, MD , is the Chaney Family Endowed Chair in Ophthalmology Research and Professor of Ophthalmology at the Cole Eye Institute, Cleveland Clinic, and is Founding Director of the Digital Optical Coherence Tomography Reading Center, both in Cleveland, OH. Jeff rey S. Heier, MD , is the co-president and medical director of Ophthalmic Consultants of Boston, in Boston, MA. Peter A. Campochiaro, MD , is the Eccles Professor of Ophthalmology and Neuroscience at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, in Baltimore, MD. FUNCTIONS OF THE TIE2 PATHWAY PRAVIN U. DUGEL, MD This path- way is complex, so let's begin with the basics. Dr. Campochiaro, can you please outline the Tie2 pathway and its impor- tance in the body? PETER A. CAMPOCHIARO, MD Tie2 is a tyrosine kinase receptor expressed primarily in the vascular endothelium, and it plays a very important role in vas- cular development. Without either Tie2 or its binding partners, angiopoietin-1 or angiopoietin-2 (Ang-1 and Ang-2, respectively), vascular development is abnormal. 2 is pathway is critical for the development of normal blood vessels, and in adults, it is important for vascular stabilization. Tie2 is constitutively activated by Ang-1 in endothelial cells throughout the body, resulting in a cascade of events that help maintain a stable, quiescent vasculature. 2 In the retina, activated Tie2 controls endothelial cell proliferation, barrier function, and intercellular contacts, stabilizing vessels and the blood-retinal barrier. 3 Tie2 is THE TIE2 PATHWAY: What Retina Specialists Need to Know Report of a Roundtable Discussion held July 13, 2017 MODERATOR Pravin U. Dugel, MD , is managing partner of Retinal Consultants of Arizona in Phoenix, AZ; clinical professor at the USC Roski Eye Institute, University of Southern California Keck School of Medicine, Los Angeles, CA; founding member of Spectra Eye Institute in Sun City, AZ; and physician executive director of the Banner Eye Institute, University of Arizona, in Phoenix, AZ. inactivated in certain disease processes, which allows for vascular leakage and pathologic angiogenesis. 2 DUGEL Can you describe what is meant by "vascular stabilization" in more detail? CAMPOCHIARO A stable vasculature is one in which vessels are operating in a state of homeostasis. Pericytes, endothe- lial cell junctions, and the extracellular matrix are intact. A stable vasculature, particularly in the retina, is non-leaking: it does not allow plasma or bone mar- row-derived cells into the tissue, nor does it respond to transient fl uctuations in stimulating factors such as VEGF. Indeed, as it pertains to this pathway, in order for the vascular endothelium to be stimulated by VEGF, Tie2 has to be downregulated. 2-4 So in a sense, Tie2 acts as a sort of rheostat to control how much the endothelial cells will respond to other stimulating factors. 4 VEGF is thought to be the primary stimulus for both vascular leakage and pathologic angio- genesis; when activated, the Tie2 pathway counters that by reducing the endothelial cell response to VEGF. 4,5 DUGEL How is the Tie2 pathway regulated? PETER K. KAISER, MD Unlike the VEGF pathway, there are a couple of regulators of Tie2. e fi rst class of regulators are the angiopoietins, Ang-1 and Ang-2. Ang-1 is the endogenous agonist for Tie2: when Ang-1 binds and stimulates phosphorylation of Tie2, it initiates a cascade of signaling pathways that ultimately lead to vascular stability. 2,5 We can think of Ang-2 as an antago- nist, though it is actually a partial agonist. 6 Ang-2 binds to Tie2, but does not lead to its phosphorylation. us, in most cases, Ang-2 works by blocking Ang-1 and Over the past few decades, un- derstanding the role of vascular endothelial growth factor (VEGF)— including the development of anti-VEGF agents—has revolution- ized treatment of diseases such as age-related macular degeneration (AMD) and diabetic macular edema (DME). But in spite of the benefi ts achieved with VEGF suppression, many patients have a suboptimal response, underscoring the need to identify and address other therapeutic targets. 1 Emerging basic science and clinical research are revealing a diff erent pathway and set of therapeutic targets: the tyrosine kinase receptor, Tie2, and its negative regulators, including vascular endothelial-protein tyrosine phosphatase (VE-PTP) and angiopoietin-2 (Ang-2). In this expert roundtable discus- sion, we will review what is known about the Tie2 pathway, its signif- icance in retinal vasculopathies, and the therapeutic approaches currently under investigation to manipulate its activity. We will diff erentiate and discuss the status of clinical research into these approaches, and fi nally, contextu- alize our expectations for how they will impact clinical practice. Ang-1 is the endogenous agonist for Tie2: when Ang-1 binds and stimulates phosphorylation of Tie2, it initiates a cascade of signaling pathways that ultimately lead to vascular stability.

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