In the 20 or so years he’s studied eye disease, Ganesh Prasanna—an associate director of ophthalmology at the Novartis Institutes for BioMedical Research (NIBR)—has seen big shifts in how doctors and scientists approach glaucoma. But it hasn’t been enough. Glaucoma remains the second leading cause of blindness in the world, and it affects some 60 million people worldwide. We know it robs sight—beginning with peripheral vision—but we don’t know why. While it’s associated with increased pressure in the eye, there’s a maxim in science: correlation isn’t necessarily causation.
I sat down with Prasanna to learn more about where glaucoma research has been, how we move from what happens in the eye to why, and whether we should use the word “cure.”
Where did things stand when you first got into eye research?
Just before I got into the field, eye doctors started prescribing drugs called prostaglandins, the first drugs developed specifically for glaucoma. Until then, the best treatments were repurposed from heart disease, which also involves changes in pressure, just in the blood. Twenty years later, prostaglandins remain the standard of care. But they haven’t been the solution we’d hoped for. Patients with glaucoma are still going blind.
Why is that?
The biggest issue is that we are not tackling the roots of the disease. Today’s treatments go after the elevated eye pressure associated with glaucoma. But they don’t address the whole picture.
How do you mean?
We need to understand at a basic, cellular level what disease-related changes the eye experiences, and ask why they happen. What pathological changes occur within the cells that regulate fluid movement behind the cornea, thereby increasing pressure? How do these cells control pressure in the first place?
And how, fundamentally, does pressure affect the retina? We know that retinal ganglion cells at the back of the eye—which send visual information back to the brain through the optic nerve—progressively die off in glaucoma patients, but we don’t know why.
What’s kept us from finding out?
A big obstacle has been a historic lack of tissues available for study. In the oncology field, you can take biopsies. You can sample the same patient over time to look for ongoing changes.
With glaucoma, you can’t do that. You can’t biopsy someone’s eye unless they’re having eye surgery. And for a long time people just didn’t know they could donate their eyes for research after they died. When people did donate, most often it was for cornea transplants. Once the cornea was collected, the rest of the eye was discarded.
What’s changed?
Very good relationships with eye banks have been key to the field as a whole. It’s increased access to patient samples, which has let researchers start to build complex models and simulate in the laboratory what happens to the eye. We’re learning just how complex and multifactorial glaucoma is.
So the field has a better starting point to work from now.
Yes. Now we can start doing fancy things like deep RNA sequencing, and compare which genes are on and off in cells from healthy eyes and diseased eyes. We can ask whether cells from glaucoma patients produce different profiles of proteins, lipids, pro- and anti-oxidants, etc., and see whether those factors cause eye pressure to go up or down, or affect the cells in the retina—specifically, retinal ganglion cells.
With these new capabilities, what do you want to discover?
Four things. First, targets for more effective, longer-lasting pressure-lowering drugs, ones with fewer side effects and which can be given in ways that encourages patient compliance.
Second, how to save retinal ganglion cells and prevent the damage from getting worse.
Third, ways of identifying patients earlier, of predicting whether this person or that person is more likely to get glaucoma. That way we can intervene sooner and prevent a patient’s vision from deteriorating further.
Fourth, surrogate diagnostics that can reliably predict how a patient will progress and quickly tell if a treatment is working.
So far in our conversation, you have yet to use the word, “cure.”
I’d love to cure glaucoma. But I’m a realist, in that I see the value of making small yet meaningful steps and approaching glaucoma in a systematic manner. People in the past took a one-size-fits-all approach, thinking that because the pressure is controlled, all is well. That hasn’t been very successful because glaucoma continues to blind people.
Main image: Researchers are building models with retinal ganglion cells (shown here as red and green dots) to learn more about the molecular mechanisms of glaucoma. The cells in this image are from mice. Image: Chenying Guo, Novartis
