Many of the world's leading causes of irreversible blindness, including glaucoma and age-related macular degeneration, share a common problem: the buildup of fluid, waste and inflammatory debris in the back of the eye.
However, for decades, scientists have lacked a clear understanding of how the eye clears this waste away.
New research from the University of British Columbia and the University of Toronto has identified what appears to be a missing piece of the puzzle: a previously unknown waste drainage system at the back of the eye. The hidden circulatory pathway, called the posterior ocular lymphatic outflow, or POLO pathway, provides a route for fluid and waste to exit the eye and enter the body's lymphatic system.
"The retina is one of the most metabolically active parts of the body, constantly generating byproducts that need to be cleared," said Dr. Neeru Gupta, professor and head of UBC's department of ophthalmology and visual sciences. "This discovery helps explain how the eye flushes this waste and promises to transform how we think about and treat a range of eye conditions."
A foundation for future therapies
Diseases like glaucoma, macular degeneration and retinal disorders are all associated with fluid buildup, accumulation of metabolic waste, and tissue stress and inflammation. Age-related macular degeneration alone affects approximately 2.5 million Canadians.
The discovery of the POLO pathway suggests there is a natural system responsible for clearing this material and opens new opportunities to harness this system to treat disease.
"This gives us a whole new framework for understanding these diseases and a potential target for therapeutics," said Dr. Gupta. "The question now is: How can we enhance or exploit this cleanup system to treat or even prevent disease."
Hiding in plain sight
For more than a century, the eye was thought to lack a lymphatic system, which is present in nearly every other organ and helps to regulate fluid, remove waste and support immune function.
Dr. Gupta and Dr. Yeni Yücel, professor and director of ophthalmic pathology at the University of Toronto, began challenging that idea in 2009 with the discovery of a lymphatic-related drainage pathway at the front of the eye, termed the "uveolymphatic" pathway. Yet the back of the eye, where many blinding diseases are rooted, has remained largely unexplored.
"The retina is responsible for vision and it's also where many of the most serious vision-loss diseases occur," said Dr. Yücel. "Understanding how this part of the eye maintains a balanced environment and flow of materials is critical."
To uncover the POLO pathway, the team used advanced imaging in mice, combining MRI, near-infrared fluorescence and microscopic analysis. They introduced fluorescent tracer molecules into a thin space at the back of the eye and tracked their movement in real time.
This allowed them to identify small lymphatic vessels in the choroid, a thin layer beneath the retina. Fluid drained from the back of the eye into surrounding orbital tissue and, within minutes, reached nearby lymph nodes that link the eye to the broader lymphatic system.
"Because lymphatic vessels in the choroid were thought not to exist, the team used multiple techniques to demonstrate both their presence and function," added Dr. Yücel, a pathologist-scientist at St. Michael's Hospital. "We were surprised to see such a direct route for fluid to leave the eye and connect with the lymphatic system. It suggests the back of the eye has an active clearance pathway, which could play an important role in removing fluid, proteins and inflammatory material that build up in disease."
Further research is needed to understand how the lymphatic pathway operates in humans and how it could be targeted with therapeutics.
But the researchers say it could one day lead to improved drug delivery to the back of the eye, new therapies that enhance fluid clearance, and deeper insight into how pressure, inflammation and fluid dynamics contribute to vision loss.
"This is a foundational discovery that shows the eye is not as closed a system as we previously thought," said Dr. Gupta. "It gives us a new map, a new mechanism and a new set of questions to explore."
The study was published today in Translational Vision Science & Technology [LINK].
The research was supported by the Canadian Institutes of Health Research, Glaucoma Research Society of Canada, Henry Farrugia Ophthalmology Research Fund, Canadian Space Agency, Dorothy Pitts Chair, Stephen M. Drance Chair, Thor and Nicky Eaton Research Fund and Canada Foundation for Innovation Leaders Opportunity Fund.
