Vitamin B ₃ protects mice from glaucoma: Glaucoma is the most common cause of age-related blindness in the United States. There is currently no cure, and once vision is lost, the condition is irreversible. Williams et al. now report that vitamin B ₃ (also known as niacin) prevents eye degeneration in glaucoma-prone mice (see the Perspective by Crowston and Trounce). Supplementing the diets of young mice with vitamin B ₃ averted early signs of glaucoma. Vitamin B ₃ also halted further glaucoma development in aged mice that already showed signs of the disease. Thus, healthy intake of vitamin B ₃ may protect eyesight. Science , this issue p. 756 ; see also p. 688

Importance: Retinal ganglion cells endure significant metabolic stress in glaucoma but maintain capacity to recover function. Nicotinamide, a precursor of NAD⁺, is low in serum of glaucoma patients and its supplementation provides robust protection of retinal ganglion cells in preclinical models. However, the potential of nicotinamide in human glaucoma is unknown.Background: To examine the effects of nicotinamide on inner retinal function in glaucoma, in participants receiving concurrent glaucoma therapy.Design: Crossover, double‐masked, randomized clinical trial. Participants recruited from two tertiary care centres.Participants: Fifty‐seven participants, diagnosed and treated for glaucoma.Methods: Participants received oral placebo or nicotinamide and reviewed six‐weekly. Participants commenced 6 weeks of 1.5 g/day then 6 weeks of 3.0 g/day followed by crossover without washout. Visual function measured using electroretinography and perimetry.Main outcome measures: Change in inner retinal function, determined by photopic negative response (PhNR) parameters: saturated PhNR amplitude (Vmax), ratio of PhNR/b‐wave amplitude (Vmax ratio).Results: PhNR Vmax improved beyond 95% coefficient of repeatability in 23% of participants following nicotinamide vs 9% on placebo. Overall, Vmax improved by 14.8% [95% CI: 2.8%, 26.9%], (P = .02) on nicotinamide and 5.2% [−4.2%, 14.6%], (P = .27) on placebo. Vmax ratio improved by 12.6% [5.0%, 20.2%], (P = .002) following nicotinamide, 3.6% [−3.4%, 10.5%], (P = .30) on placebo. A trend for improved visual field mean deviation was observed with 27% improving ≥1 dB on nicotinamide and fewer deteriorating (4%) compared to placebo (P = .02).Conclusions: Nicotinamide supplementation can improve inner retinal function in glaucoma. Further studies underway to elucidate the effects of long‐term nicotinamide supplementation.

Nicotinamide adenine dinucleotide (NAD) is a REDOX cofactor and metabolite essential for neuronal survival. Glaucoma is a common neurodegenerative disease in which neuronal levels of NAD decline. We assess the effects of nicotinamide (a precursor to NAD) on retinal ganglion cells (the affected neuron in glaucoma) in normal physiological conditions and across a range of glaucoma relevant insults including mitochondrial stress and axon degenerative insults. We demonstrate retinal ganglion cell somal, axonal, and dendritic neuroprotection by nicotinamide in rodent models which represent isolated ocular hypertensive, axon degenerative, and mitochondrial degenerative insults. We performed metabolomics enriched for small molecular weight metabolites for the retina, optic nerve, and superior colliculus which demonstrates that ocular hypertension induces widespread metabolic disruption, including consistent changes to α-ketoglutaric acid, creatine/creatinine, homocysteine, and glycerophosphocholine. This metabolic disruption is prevented by nicotinamide. Nicotinamide provides further neuroprotective effects by increasing oxidative phosphorylation, buffering and preventing metabolic stress, and increasing mitochondrial size and motility whilst simultaneously dampening action potential firing frequency. These data support continued determination of the utility of long-term nicotinamide treatment as a neuroprotective therapy for human glaucoma.

Primary open-angle glaucoma (POAG) is a leading cause of irreversible vision loss, yet much of the genetic risk remains unaccounted for, especially in African-Americans who have a higher risk for developing POAG. We conduct a multiethnic genome-wide association study (GWAS) of POAG in the GERA cohort, with replication in the UK Biobank (UKB), and vice versa, GWAS in UKB with replication in GERA. We identify 24 loci (P < 5.0 × 10⁻⁸), including 14 novel, of which 9 replicate (near FMNL2, PDE7B, TMTC2, IKZF2, CADM2, DGKG, ANKH, EXOC2, and LMX1B). Functional studies support intraocular pressure-related influences of FMNL2 and LMX1B, with certain Lmx1b mutations causing high IOP and glaucoma resembling POAG in mice. The newly identified loci increase the proportion of variance explained in each GERA race/ethnicity group, with the largest gain in African-Americans (0.5–3.1%). A meta-analysis combining GERA and UKB identifies 24 additional loci. Our study provides important insights into glaucoma pathogenesis.

Glaucoma is a complex, multifactorial disease characterised by the loss of retinal ganglion cells and their axons leading to a decrease in visual function. The earliest events that damage retinal ganglion cells in glaucoma are currently unknown. Retinal ganglion cell death appears to be compartmentalised, with soma, dendrite and axon changes potentially occurring through different mechanisms. There is mounting evidence from other neurodegenerative diseases suggesting that neuronal dendrites undergo a prolonged period of atrophy, including the pruning of synapses, prior to cell loss. In addition, recent evidence has shown the role of the complement cascade in synaptic pruning in glaucoma and other diseases. Using a genetic (DBA/2J mouse) and an inducible (rat microbead) model of glaucoma we first demonstrate that there is loss of retinal ganglion cell synapses and dendrites at time points that precede axon or soma loss. We next determine the role of complement component 1 (C1) in early synaptic loss and dendritic atrophy during glaucoma. Using a genetic knockout of C1qa (D2.C1qa -/- mouse) or pharmacological inhibition of C1 (in the rat bead model) we show that inhibition of C1 is sufficient to preserve dendritic and synaptic architecture. This study further supports assessing the potential for complement-modulating therapeutics for the prevention of retinal ganglion cell degeneration in glaucoma.