One of the most effective treatments for glaucoma, latanoprost, was developed by Columbia ophthalmology researcher Laszlo Bito, PhD, who in the 70s and 80s conducted the key studies that led to the drug’s approval in 1996. Since then, latanoprost has been the first-line treatment for reducing pressure inside the eye and preventing retinal damage and blindness.
Though the drug has saved the sight of millions of people, Simon John, PhD, a glaucoma researcher at Columbia, says there’s still room for improvement. “In some people, glaucoma progresses even at normal pressure, and many of these people are at risk of vision loss,” says John, the Robert L. Burch III Professor of Ophthalmic Sciences at the Vagelos College of Physicians and Surgeons.
Like Bito, whose ideas were at first dismissed by most glaucoma researchers, John initially encountered stiff resistance to his approach to studying glaucoma. “The resistance provided a challenge, and challenges tend to drive me,” says John, whose methods were eventually accepted and widely adopted.
John’s methods and observations have led to fundamental change in the way ophthalmologists think about glaucoma and to a potentially simple intervention: vitamin B3 and pyruvate.
We spoke with John about the nutrients’ potential to prevent glaucoma and about his approach to science.
What led you to the idea that vitamin B3 and pyruvate can prevent glaucoma?
We had characterized mice with high intraocular pressure that were likely to develop glaucoma but had not yet developed it. With those mice, we could look at what happens in the eye in the early stages of disease before any signs of retinal damage appear.
And one of the first changes we observed was mitochondrial dysfunction in retinal ganglion cells, which suggested mitochondria might be a primary driver of glaucoma. We also found that as the mice aged, levels of NAD, a molecule that promotes mitochondria health and balanced energetic metabolism declined.
I can recall a conversation with my mentor, Oliver Smithies, who shared the Nobel Prize in Physiology or Medicine in 2007. As we discussed experimental options, he strongly advocated for testing vitamin B3 supplementation. Vitamin B3 is a major precursor of NAD.
Not only did vitamin B3 supplements boost NAD levels in our mice, but many fewer of the mice with high intraocular pressure and these higher NAD levels developed glaucoma. We observed a similar protective effect with another metabolite that balances metabolism, pyruvate.
With additional experiments, we showed that vitamin B3 and pyruvate in combination are more protective than either nutrient alone.
This reinforced our concept of metabolic neuroprotection—building cellular resilience by rebalancing metabolism so that retinal cells function better and are more able to protect and repair themselves when exposed to damaging processes. Further supporting this, in a more recent collaborative study, we found that pyruvate and other energetic metabolites protect from high genetic risk for glaucoma in humans.
This is an exciting result. Could the same intervention work in people?
We conducted a small clinical trial here—led by Carlos Gustavo De Moraes, Jack Cioffi, and Jeffrey Liebmann—and the results were very promising. We administered vitamin B3 and pyruvate to 21 patients with glaucoma and moderate visual field loss in at least one eye. Over the course of a few months, we observed significant improvements in visual function.
This has prompted ophthalmologists around the world to test the idea in additional clinical trials. To date, results from three independent trials have been published, all demonstrating a positive outcome.
At Columbia, a second longer term trial is underway led by Aakriti Shukla and our original clinical team. Longer trials around the world are now determining whether metabolic neuroprotection is effective over the long term and how broadly it may reduce disease severity.
Because this approach aims to make retinal cells more resilient to the damaging stresses of aging and glaucoma, its benefits are not expected to be limited to patients with specific glaucoma genes. With positive outcomes from these trials, the treatment could become important for a large number of people. Furthermore, our metabolic treatments work by improving molecular processes that are unaddressed by established treatments. This is important as it means that metabolic neuroprotection has strong potential to augment and complement current state-of-the-art treatments.
Beyond treating patients, I believe metabolic support through dietary supplementation of these bioenergetic molecules could eventually have a prophylactic role in the general population. Given all of this, I am highly motivated to push further research with the goals of improving efficacy, while using safer lower doses. To do this, we plan to develop cocktails of resilience-inducing agents with a focus on natural molecules and their derivatives. Currently, the most effective doses in animals are not safe for people, while the higher doses used in clinical trials are generally safe but require physician-monitored blood tests due to potential adverse effects.
Do you think there will be additional ways to treat glaucoma?
We’re just at the beginning. We do not yet know all the possible pharmacologic interventions. As we learn more about the biology of glaucoma, we could discover molecules that are even more potent than vitamin B3 or pyruvate.
We’ve recently discovered that the blood-retinal barrier—almost completely ignored by our field—could be a major player in glaucoma. We found that high eye pressure compromises the blood–retinal barrier, allowing small molecules to leak into the eye and contribute to vision loss—a process not detected by standard glaucoma tests in the clinic, which may explain why it has been overlooked.
Several drugs are being developed by various companies to promote the integrity of the blood-brain and blood-retina barriers for other conditions, including diabetes. Our work raises the exciting possibility that these drugs could be rapidly redeployed for glaucoma.
You pioneered using mice in glaucoma research. At that early stage, how did experts in the field respond to your ideas?
Mice are very powerful tools in the study of disease. Despite remaining doubts by some, our findings in mice have repeatedly preceded similar findings in humans. Some of our major findings in mice are now translating in clinical trials, as we discussed earlier. The problem was the dogma, at the time, that the mouse eye was a poor analog of the human eye. For example, it was often said that mice lacked a true Schlemm’s canal, an important structure responsible for regulating intraocular pressure. It was also believed that structural differences in the mouse’s optic nerve precluded the development of glaucoma.
I listened to these arguments and was a bit put off. But I gathered myself, thought hard, and decided to evaluate the evidence for myself. Over a period of many months, I scoured old literature and eventually concluded that there was no convincing evidence against using mice.
We worked out the pertinent anatomy and found that mice do indeed have a Schlemm’s canal and that their optic nerve structure does not preclude developing glaucoma. We published our findings, and today mice are routinely used in glaucoma research.
As a result, I often tell trainees to consider the views of others, but don’t be too put off by experts and dogma. If you’ve done your reading and data analysis and are still convinced something is worth doing, then trust your instincts and act boldly. Ultimately, the quality of your data and findings will speak for themselves.
The man behind latanoprost
When Columbia researcher Laszlo Bito began studying glaucoma, it was assumed by virtually every expert in the field that hormones called prostaglandins raised pressure inside the eye (intraocular pressure, or IOP). Bito was unconvinced, and he went on to prove just the opposite.
With careful experimentation on animals and even on himself, Bito showed that at very small doses, prostaglandins applied directly to the eye could lower intraocular pressure. This observation led to the development of a synthetic prostaglandin, latanoprost, which remains the standard treatment for glaucoma. Bito died in November 2021 at the age of 87.
