Genetic basis of glaucoma

Northwestern Medicine scientists and international collaborators discovered mutations that cause improper drainage and a buildup of ocular pressure leading to one form of congenital glaucoma, and identified a path towards future treatments for the disease. Susan Quaggin, MD, chief of Nephrology and Hypertension in the Department of Medicine and director of the Feinberg Cardiovascular Research Institute, was senior author on the studies.

Glaucoma is a leading cause of blindness around the globe, and elevated intraocular pressure (IOP) is an important risk factor for the disease. Developmental defects in the anterior chamber of the eye, including a drainage vessel called Schlemm's canal, can lead to a particularly severe form of glaucoma in children known as primary congenital glaucoma (PCG).

Previous studies from Quaggin and her collaborators have shown loss-of-function mutations in the angiopoietin (ANGPT) receptor TIE2/TEK in families with PCG, and that ANGPT/TIE2 pathway activity is critical for Schlemm's canal development.

 In the JCI study, Quaggin and her colleagues used mice models to explore the importance of individual components of the ANGPT/TEK pathway, finding mice without the growth factor ANGPT1 had severely deformed and small Schelmm's canals. In addition, loss of TIE2/TEK, the angiopoietin receptor, had a similar effect.

Both ANGPT1 and TIE2/TEK are essential to form the drainage system of the eye to regulate intraocular pressure and prevent Glaucoma. Researchers found two human subjects with loss-of-function mutations in ANGPT1 within an international group of PCG patients, further supporting a causative role for ANGPT1 in the disease.

In the PNAS study, Quaggin and her colleagues searched for ways to influence the molecular pathway they'd identified. In particular, inhibition of TIE2/TEK has been linked to vessel leakage and inflammation, so finding a way to activate TIE2/TEK was a priority. Using mouse models, investigators found inhibition of a protein called VEPTP allowed ANGPT2 to be used as a TIE2/TEK activator, providing a blueprint for a pharmacological solution.
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