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Targeting Tie2 for Treatment of Diabetic Retinopathy and Diabetic Macular Edema

  • Microvascular Complications—Retinopathy (JK Sun and PS Silva, Section Editors)
  • Published:
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Abstract

Tie2 is a tyrosine kinase receptor located predominantly on vascular endothelial cells that plays a central role in vascular stability. Angiopoietin-1 (Angpt1), produced by perivascular cells, binds, clusters, and activates Tie2, leading to Tie2 autophosphorylation and downstream signaling. Activated Tie2 increases endothelial cell survival, adhesion, and cell junction integrity, thereby stabilizing the vasculature. Angiopoietin-2 (Angpt2) and vascular endothelial-protein tyrosine phosphatase (VE-PTP) are negative regulators increased by hypoxia; they inactivate Tie2, destabilizing the vasculature and increasing responsiveness to vascular endothelial growth factor (VEGF) and other inflammatory cytokines that stimulate vascular leakage and neovascularization. AKB-9778 is a small-molecule antagonist of VE-PTP which increases phosphorylation of Tie2 even in the presence of high Angpt2 levels. In preclinical studies, AKB-9778 reduced VEGF-induced leakage and ocular neovascularization (NV) and showed additive benefit when combined with VEGF suppression. In two clinical trials in diabetic macular edema (DME) patients, subcutaneous injections of AKB-9778 were safe and provided added benefit to VEGF suppression. Preliminary data suggest that AKB-9778 monotherapy improves diabetic retinopathy. These data suggest that Tie2 activation may be a valuable strategy to treat or prevent diabetic retinopathy.

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Authors and Affiliations

  1. Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Peter A. Campochiaro

  2. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Peter A. Campochiaro

  3. The Wilmer Eye Institute, The Johns Hopkins School of Medicine, 815 Maumenee, 600 N. Wolfe Street, Baltimore, MD, 21287-9277, USA

    Peter A. Campochiaro

  4. Aerpio Therapeutics, 9987 Carver Road, Cincinnati, OH, USA

    Kevin G. Peters

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Correspondence to Peter A. Campochiaro.

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Conflict of Interest

Peter A. Campochiaro reports grants and other from Aerpio Therapeutics, grants and other from Regeneron Therapeutics, grants and other from Genentech/Roche, grants and personal fees from Alimera, grants and personal fees from Allergan, personal fees from Applied Genetic Technologies, grants and personal fees from AsclepiX, grants and personal fees from Rxi, personal fees from Allegro, personal fees from Intrexon, grants and personal fees from Regenxbio, grants from AbbVie, grants from Genzyme, grants from GlaxoSmithKline, grants from Oxford Biomedica, personal fees and other from Graybug, and personal fees from Merck.

Kevin G. Peters is an employee of Aerpio Therapeutics. In addition, Dr. Peters is an inventor on issued and pending composition of matter and methods of use patents for AKB-9778.

Human and Animal Rights and Informed Consent

The clinical trials discussed in this manuscript were approved by the appropriate institutional and/or national research ethics committee and were performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

All procedures performed in studies involving animals were in accordance with the ethical standards of the Johns Hopkins University School of Medicine where the studies were conducted.

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This article is part of the Topical Collection on Microvascular Complications—Retinopathy

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Campochiaro, P.A., Peters, K.G. Targeting Tie2 for Treatment of Diabetic Retinopathy and Diabetic Macular Edema. Curr Diab Rep 16, 126 (2016). https://doi.org/10.1007/s11892-016-0816-5

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