Pressure point

EYE PRESSURE is a major risk factor for glaucoma. Whether starting with high eye pressure or even “normal” eye pressure, something about the eye pressure causes ongoing damage to the optic nerve leading to vision loss in patients with glaucoma. Current medications and surgeries for the disease address the production and drainage of fluid from the eyes to help lower this pressure. But no one knows how eye pressure leads to optic nerve degeneration. 

Stanford researchers, led by physician-scientist Wendy Liu, MD, PhD, assistant professor of ophthalmology, are seeking a way to understand the fundamental element of eye pressure in this disease, and thereby develop new therapies. 

“Rather than working so hard to externally control the eye pressure, if we could target the eye's pressure sensors to teach the eye to set the pressure lower by itself, it would be a completely new way of thinking about treating glaucoma,” Liu said. “We need to find the eye’s pressure sensor and discover how to adjust it.”

In addition to pressure sensors in the eye having the potential to better control the eye pressure, as yet unknown molecular sensors in the eye must also be transducing pressure into damage. “If we can discover the fundamental mechanisms by which the eye or optic nerve degenerates in response to pressure in some patients, we could shut off that path and make patients resistant,” Liu said.

What are the pressure sensing genes and proteins, then? Using data from the NEIGHBORHOOD Consortium for glaucoma genetics, Liu and her team, in collaboration with Janey Wiggs, MD, PhD, professor of ophthalmology at the Massachusetts Eye and Ear Infirmary, analyzed genetic variants associated with glaucoma in 3,853 people with primary open-angle glaucoma and 33,480 controls. The team identified variants in mechanosensitive ion channel genes that may be the target they are seeking. 

“Mechanosensitive ion channels are basically molecular pressure sensors, and now we have some genetic data showing that certain variants of these genes are associated with the risk of developing glaucoma,” Liu said.

In ongoing research, Liu and her team are testing the function of these genes in cell culture and animal models of glaucoma. Liu’s research collaborators include Jeffrey Goldberg, MD, PhD, Blumenkranz Smead professor and chair of ophthalmology; Stephen Baccus, PhD, professor of neurobiology; and other faculty from these departments. Pilot funding for the project comes from the American Glaucoma Society, Research to Prevent Blindness, and a Stanford KL2 Career Development Award. 

"If we show that these variants alter the course of glaucoma in animal models, that would provide supporting evidence that this would be a viable drug target for glaucoma," Liu said. 

Ultimately, the research findings could lead to new targeted therapies for glaucoma that could alter the function of these pressure sensors to prevent disease progression. 

Post-surgical scarring 

In other research, Liu and her colleagues are looking to solve a more downstream problem in glaucoma care: post-surgical scarring. Trabeculectomy is considered the gold standard glaucoma surgical procedure for lowering eye pressure, but the most common reason that trabeculectomy fails over time is scarring. 

In trabeculectomy, the surgeon creates a new drainage channel in the sclera, creating a fluid pocket (called a “bleb”) beneath the conjunctiva to reduce pressure and prevent further vision loss. But if a scar forms between the conjunctiva and the sclera, a common complication that can occur months or years after surgery, the drainage channel can no longer effectively lower intraocular pressure. 

In a project funded by Stanford’s SPARK program, which provides grants to generate proof-of-concept data as well as access to specialized knowledge and technical expertise regarding drug development to support translational research, and the American Glaucoma Society, Liu and her team are testing a new drug to determine whether it might help prevent post-surgical scarring in glaucoma patients. 

"If it works, we could prolong the survival of glaucoma surgeries and improve outcomes for patients," Liu said.

As a physician-scientist, Liu looks forward to a time when discoveries made in her lab will benefit patients in her clinic.

"Hearing patients’ stories in the clinic motivates me to discover more about the disease,” Liu said. “Hopefully we can take this clinically relevant data and translate it into discoveries and eventually treatments that can help patients maintain their vision for a lifetime.”