Administrative Supplement for Research on Vitamin B3 Dietary Supplements for Eye Disease

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Abstract: Vitamin B3 (nicotinamide) is a widely available dietary supplement that is often marketed as an anti-aging agent. Scientific studies of vitamin B3 have largely centered on its role as a precursor to nicotinamide adenine dinucleotide (NAD+), a coenzyme and co-substrate that is key to cellular metabolism. Reductions in NAD+ levels are thought to be linked to reduced mitochondrial efficiency and to promote numerous diseases. Conversely, strategies which increase cellular NAD+ levels―such as vitamin B3 dietary supplementation―might promote health and prevent disease. Our currently proposed studies derive from scientific work that has begun to test this framework for the blinding eye disease, glaucoma. Glaucoma is a group of age-related neurodegenerative diseases characterized by loss of retinal ganglion cells (RGCs) and their axons that is often precipitated by elevated intraocular pressure (IOP). Because RGCs are post-mitotic neurons, their loss is permanent and causes a gradual decline leading toward irreversible blindness. A 2017 paper in the journal Science suggested that an age-related decline of NAD+ in the retina might render RGCs susceptible to glaucoma and that dietary supplementation of vitamin B3 lessened disease severity in one widely used mouse model of glaucoma (the DBA/2J model). Follow-up studies have begun to test additional agents which modulate NAD+, such as nicotinamide riboside; to examine mouse models with other forms of ocular disease; and some clinical trials have advanced to phase 2. Despite these advances, there are many unanswered questions regarding the significance, model specificity, and mechanisms of these findings. In 2019 our Glaucoma Center initiated a replication study of DBA/2J mice treated with nicotinamide and began a parallel study with the nee mouse model of severe congenital glaucoma. Unfortunately, challenges related to the COVID-19 pandemic prevented us from completing these experiments. This administrative supplement for R01EY030366 “Novel Genome Editing for the Treatment of Glaucoma”, will allow us to complete the quantitative assessment of the optic nerves from these mice. We will also examine how dietary vitamin B3 alters IOP―an important but under studied question. Specifically, we will test whether there is an interaction between ATF4 activated pathways and nicotinamide. This supplement will enhance our parent award and move us toward improved glaucoma therapies by completing an important replication study with DBA/2J mice using quantitative assessments of axon number, completing a test of neuroprotection in nee mice with severe glaucoma, and testing a mechanism relevant to both ATF4 and nicotinamide in influencing IOP.