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Editors Selection IGR 15-4

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Comment by Keith Martin on:

71509 Vitamin B3 modulates mitochondrial vulnerability and prevents glaucoma in aged mice, Williams PA; Harder JM; Foxworth NE et al., Science, 2017; 355: 756-760

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Many patients with glaucoma continue to experience progressive visual loss despite treatment to lower their eye pressure and thus the development of new therapeutic strategies to protect the vision of such patients remains an important goal. The paper by Williams et al. describes the novel finding that a reduced level of nicotinamide adenine dinucleotide (NAD) in aged mice is an important risk factor for retinal ganglion cell loss. The researchers studied DBA/2J mice, a strain which develops an eye condition with similarities to pigmentary glaucoma. They found that dietary supplementation with nicotinamide, a precursor of NAD, or gene therapy to drive the expression of a NAD-generating enzyme [nicotinamide nucleotide adenylyltransferase 1 (Nmnat1)] could both effectively halt glaucomatous disease progression in these animals. The strength of the neuroprotective effect obtained by manipulation of a single molecule was truly remarkable, and the additional observation that the higher dose of dietary nicotinamide also decreased eye pressure in the DBA/2J mice was also interesting, hinting at a possible dual mechanism of action.

Another interesting question that arises from this work whether the site of protective action by NAM and NMNAT1 is in the cell body, the axon or both. A nuclear site of action might be suggested by previous observations that DNA damage by PARP1 depletes nuclear NAD and NMNAT1, and is a nuclear enzyme that fails to protect injured axons in transgenic mice unless it is excluded from nuclei. However an axonal action would also appear conceivable and it would be interesting to explore this issue in future studies.

As for many studies in animal models of glaucoma, a key consideration is how generalizable the results are to human glaucoma

As for many studies in animal models of glaucoma, a key consideration is how generalizable the results are to human glaucoma. All models, including DBA/2J, have limitations and it is good that the authors also tested their therapeutic approach in a tissue culture model of axotomy and in a model involving intravitreal injection of TNF alpha. Replication of the results in other models would give increased confidence that these results could be relevant to humans, but the real answer will come from human clinical trials which would appear to be feasible and realistic. As a prelude to human studies, it will be important to determine if the very doses used in this proof-of-concept study are required to achieve a therapeutic effect.

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