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.

The study was first published in the  Journal of Clinical Investigation (JCI) and the second published in the  Proceedings of the National Academy of Sciences  of the United States of America (PNAS).

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).

The senior author on the studies, Susan Quaggin said, "This special vessel acts like the drainpipes in a bathtub-to prevent the eye from overfilling ." 

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.

Uncovering the genetic roots of congenital glaucoma

In the JCI study, Quaggin and her colleagues used mice 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 receptor angiopoietin, had a similar effect. "Both ANGPT1 and TIE2 / TEK are essential to the drainage system of the eye to regulate  intraocular pressure  and prevent glaucoma," Quaggin said.

"We believe it's highly likely that this pathway is also important in common IOP elevated glaucoma, with over 60 million individuals affected by this disease worldwide."

Investigators 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, according to Quaggin.

"These discoveries highlight the central role of this molecular pathway in glaucoma and provide sign posts guiding us to a new therapy," Quaggin said.

Flipping the Switch

In the  PNAS  study, Quaggin and her colleagues searched for ways to influence the molecular pathway they had 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.

"To develop a new and much needed therapy to 'fix' these vessels and lower the pressure inside the eye to prevent or treat glaucoma , we need to understand how to turn the molecules 'on' and 'off,'" Quaggin said.

Again 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, according to Quaggin.

"We are currently well underway to developing new small molecule drugs to improve drainage through the Schlemm's channel and associated outflow vessels," Quaggin said. "We are also screening other patients and looking for other mutations in the pathway."