Glaucoma affects 80 million patients globally and approximately 100,000 – 200,000 in Sweden. In glaucoma, the optic nerve, which connects the eye to the brain, is progressively damaged, often in association with elevated pressure inside the eye. The only treatment strategies currently available target the pressure in the eye using eye drops or surgery. Despite the availability of these treatments, the risk of blindness in at least one eye is still high.
What causes optic nerve degeneration in glaucoma is not entirely known, but there is currently a large focus on identifying new treatments that prevent retinal ganglion cells (the output nerves of the retina) from dying, as well as trying to repair vision loss through the regeneration of diseased nerve fibres in the optic nerve.
Previously, scientists have identified that the molecule NAD declines in the retina in an age-dependent manner and renders retinal ganglion cells susceptible to neurodegeneration. NAD is an important metabolite and an important molecule for many essential cellular processes. Preventing NAD depletion via administration of nicotinamide (the amide of vitamin B₃; a NAD precursor) robustly prevents glaucoma in chronic animal models. They also demonstrated that elevating NAD levels through nicotinamide administration can improve visual function in existing glaucoma patients.
In the current study, the scientists investigated many of the effects that nicotinamide has on the visual system (in normal conditions and during glaucoma). This is an important step for moving treatments from the lab to the clinic.
"We have confirmed nicotinamide’s neuroprotection in additional cell and animal models that recapitulate isolated features of glaucoma but are also common neurodegenerative features. We also have developed sensitive tools to investigate NAD metabolism, and the metabolism of other essential metabolites, in the visual system. We demonstrated that systemic nicotinamide administration has limited molecular side-effects, but provides a robust reversal of the disease metabolic profile of glaucoma prone animals," says James Tribble, a postdoctoral researcher in the Williams laboratory at St. Erik Eye Hospital and Karolinska Institutet, the first author of the study.
In collaboration with researchers in the USA, the research team has also developed a novel mitochondria reporter mouse, MitoV; for visual system tissue, that has fluorescent mitochondria in retinal ganglion cells. Further collaboration with teams in the UK, Denmark, and Australia allowed for a broad array of tools to investigate nicotinamide’s neuroprotection.
Photo: Johan Gunséus
"Using these varied platforms, we determined that nicotinamide provides numerous neuroprotective effects. These include buffering and preventing metabolic stress, and increasing mitochondrial size and mobility to provide an environment where retinal ganglion cells are less susceptible to glaucoma related stresses. These data support the continued determination of the utility of long-term nicotinamide treatment as a neuroprotective therapy for human glaucoma," says Pete Williams, Assistant Professor and Research Group Leader for glaucoma at Karolinska Institutet and St. Erik Eye Hospital, the senior author of the study.
In autumn 2021, the long-term clinical Swedish Glaucoma Nicotinamide Trial, lead by Umeå University, Karolinska Institutet and St. Erik Eye Hospital will begin.
"What we have demonstrated in cell and animal models is directly making its way to patients in the Swedish health care system," says Pete Williams. "This exemplifies our commitment to generating translatable treatments for glaucoma," he concludes.
The study was financed by grants from several bodies, including the Swedish Research Council, Karolinska Institutet, and St. Erik Eye Hospital philanthropic donations.
The clinical trial
Only patients with newly diagnosed and untreated glaucoma will be included in the clinical study. Either the patient's ophthalmologist can refer the patient to St. Erik Eye Hospital, or the patient's optician can, in case of suspected glaucoma, refer to Karolinska Institutet's optometry clinic at St. Erik Eye Hospital.
”Nicotinamide provides neuroprotection in glaucoma by protecting against mitochondrial and metabolic dysfunction”, James R Tribble, Amin Otmani, Shanshan Sun, Sevannah A Ellis, Gloria Cimaglia, Rupali Vohra, Melissa Jöe, Emma Lardner, Abinaya P Venkataraman, Alberto Domínguez-Vicent, Eirini Kokkali, Seungsoo Rho, Gauti Jóhannesson, Robert W Burgess, Peter G Fuerst, Rune Brautaset, Miriam Kolko, James E Morgan, Jonathan G Crowston, Marcela Votruba, and Pete A Williams, Redox Biology, online 24 April 2021, doi: 10.1016/j.redox.2021.101988.