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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Vyzulta for treating glaucoma

Vyzulta, a once daily monotherapy with a dual mechanism of action, works by metabolizing into two moieties, latanoprost acid, which primarily works within the uveoscleral pathway to increase aqueous humor outflow, and butanediol mononitrate, which releases nitric oxide NO to increase outflow through the trabecular meshwork and Schlemm's canal.

The most common ocular adverse events include conjunctival hyperemia, eye irritation, eye pain and instillation site pain. Increased pigmentation of the iris and periorbital tissue and growth of eyelashes can occur. In glaucoma patients, damage to the trabecular meshwork, through which the majority of the aqueous humor passes, can lead to reduced drainage and as a result elevated intra ocular pressure IOP. Lowering IOP, even in patients with normal baseline levels, can delay, or even prevent damage to optic nerves, helping to reduce the risk of glaucomatous visual field loss.

Preclinical studies have shown that NO plays a role in controlling IOP in normal eyes by increasing aqueous humor outflow through the trabecular meshwork and Schlemm's canal. Studies have also demonstrated that patients with glaucoma have reduced levels of NO signaling in their eyes, providing a rationale for the therapeutic value of NO-releasing molecules for patients with open-angle glaucoma or ocular hypertension.

The safety and efficacy of Vyzulta has been well-established through multiple clinical studies, which have demonstrated positive results, including statistically significant differences in IOP lowering compared to timolol and latanoprost. Vyzulta provides a new treatment option that works to reduce IOP by increasing the outflow through both the trabecular meshwork and the uveoscleral pathways.

Increased pigmentation of the iris, periorbital tissue (eyelid), and eyelashes can occur. Iris pigmentation is likely to be permanent. Gradual changes to eyelashes, including increased length, increased thickness, and number of eyelashes, may occur. These changes are usually reversible upon treatment discontinuation.
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