Dr. Laszlo Bito
In the 1970s and 1980s, the late Laszlo Bito, PhD, a renowned Columbia ophthalmology researcher, developed one of the most effective treatments for glaucoma – latanoprost – and conducted key studies that led to the drug’s approval in 1996. Since then, latanoprost has been the first-line treatment for intraocular pressure caused by open-angle glaucoma or ocular hypertension.
Though the drug has saved the sight of millions of people, Columbia glaucoma researcher Simon John, PhD, believes there is still room for improvement. “In some people, the retina degenerates even at normal pressure, and many of these people are at risk of vision loss,” says Dr. John, the Robert L. Burch III Professor of Ophthalmic Sciences (in Ophthalmology) at Columbia. Dr. John has provided a wealth of new mechanistic information and reinvigorated the field with groundbreaking research on the molecular basis of glaucoma.
Dr. Simon John
Like Dr. Bito, whose ideas were at first dismissed by most glaucoma researchers, Dr. John initially encountered resistance to his approach to studying glaucoma. “The resistance provided a challenge, and challenges tend to drive me,” says Dr. John, whose methods and observations have led to a fundamental change in the way ophthalmologists think about glaucoma and to a potentially simple intervention: vitamin B3 (nicotinamide) and pyruvate. Dr. John and colleagues in the Department of Ophthalmology at NewYork-Presbyterian/
In earlier investigations, Dr. John’s group pioneered the use of mice for glaucoma research – including adapting tools from the human clinic to mice and the development of novel tools and models. “We had characterized mice with high intraocular pressure that were likely to develop glaucoma,” says Dr. John. “With this model, we could look at what happens in the eye in the early stages of disease before any signs of retinal damage appear. One of the first changes we observed was mitochondrial dysfunction in retinal 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, declined.”
Dr. Oliver Smithies, a Nobel Prize winner and Dr. John’s mentor, strongly advocated for the introduction of vitamin B3, a major precursor of NAD, in a discussion they had about experimental treatment options. “Not only did vitamin B3 supplements boost NAD levels in our mice, but many fewer of the mice with high intraocular pressure and high NAD levels developed glaucoma,” says Dr. John, whose group observed a similar effect with pyruvate. “With additional experiments, we showed that vitamin B3 and pyruvate in combination are more protective than either nutrient alone.”
Not only did vitamin B3 supplements boost NAD levels in our mice, but many fewer of the mice with high intraocular pressure and high NAD levels developed glaucoma.
— Dr. Simon John
The phase 2 clinical trial of the nutrient combination of vitamin B3 and pyruvate conducted by the Columbia Department of Ophthalmology was led by Carlos Gustavo De Moraes, MD, PhD, MPH, Associate Professor of Ophthalmology and Medical Director of Clinical Trials; Jack Cioffi, MD, Ophthalmologist-in-Chief, NewYork-Presbyterian/
“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,” says Dr. John, who notes that researchers in other countries are achieving similar results, including a published study led by the Center for Eye Research Australia, which used vitamin B3 alone in glaucoma patients and showed improved inner retinal function.
“To extend and check our results and make sure the visual function improvements persist, we need to expand the trials to include more patients across multiple sites,” says Dr. John. “But 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.”
