Tie2 activators combined with anti-vascular endothelial growth factor therapy translate to improved anatomic function and decreased diabetic retinopathy severity scores.
Reviewed by Peter K. Kaiser, MD
Tie2, a tyrosine kinase receptor, has become an important focus of research, and when combined with vascular endothelial growth factor (VEGF) therapy the two may provide better outcomes for patients with diabetic retinopathy (DR) and diabetic macular edema (DME) than with VEGF drugs alone.
How it works
During gestation, the Tie pathway is key to the development of the ocular and vascular structures and its absence is lethal to normal development, according to Peter K. Kaiser, MD. Dr. Kaiser is the Chaney Family Endowed Chair in Ophthalmology Research, and professor of ophthalmology, Cole Eye Institute, Cleveland Clinic Lerner College of Medicine, Cleveland.
In adults, the Tie pathway is the “gatekeeper” of vascular quiescence, he noted. It regulates blood and vascular homeostasis, inflammation, and pathologic angiogenesis and has a key role in cancer and diabetes. When things are working normally, the key Tie2 ligand, angiopoietin 1 (Ang1), binds and activates Tie2, which promotes the integrity of blood vessels.
Dr. Kaiser said this is done by forming into high order oligomers that produces clustering of the Tie2 receptor required for activation. In contrast to Ang1, Ang2 is a weak agonist that is released in the presence of hypoxia, inflammation, and VEGF.
Ang2 is mainly found in dimer form and does not cause Tie2 receptor clustering and thus no receptor activation. This leads to vascular leakage, inflammation, and vascular instability. The Tie receptors are found largely on endothelial cells that provide the microenvironment in which activation can occur.
“The Tie1 receptor is an orphan receptor that regulates Tie2 receptor trafficking and is necessary for full Tie2 activation,” Dr. Kaiser said.
Peter K. Kaiser, MD
E: [email protected]
Dr. Kaiser is a consultant to Aerpio Pharmaceuticals, Allegro Ophthalmics, Bayer, Regeneron, and SciFluor.