As reported recently in Science by Simon John and his laboratory, glaucoma can be largely prevented in a mouse model of inherited glaucoma through a simple administration of nicotinamide (the amide of vitamin B3). The discovery was fueled by their observation of decreasing levels of retinal NAD and mitochondrial abnormalities in retinal ganglion cells, making them more vulnerable to degeneration in the presence of high intra-ocular pressure (IOP), the primary hallmark of glaucoma. Decreasing amounts of NAD can be mitigated by oral ingestion of nicotinamide.
The surprising finding has led to ongoing work into the precise mechanisms involved, which may provide additional therapeutic targets. In a recent paper in Frontiers in Neuroscience, John and his team present research into combining nicotinamide administration with a fusion gene variant called the Wallerian degeneration slow allele (WldS), also previously shown to decrease retinal ganglion cell vulnerability to high IOP. They demonstrated that WldS increases retinal NAD levels in mice and, in conjunction with nicotinamide, prevented glaucoma in 94% of the tested eyes, more than either WldS or nicotinamide alone. Furthermore, the protection provided by the combination therapy was comprehensive: it prevented visual dysfunction and protected all cellular compartments tested.
The protective effects of WldS are highly conserved, observed in mice, zebrafish and flies as well as in human cells. And it has the potential to mitigate axon degeneration in neurodegenerative disorders other than glaucoma. The authors conclude: “Although significant work is required before moving WldS into the clinic, based on these collective data there is definite promise for axon and synapse targeted treatments that manipulate molecules in the NAD pathway.
Williams PA et al. Nicotinamide and WLDS Act Together to Prevent Neurodegeneration in Glaucoma. Front. Neurosci. 25 April 2017, https://doi.org/10.3389/fnins.2017.00232