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Vitamin B3 prevents glaucoma, JAX researchers find

BAR HARBOR, ME--(Marketwired - February 16, 2017) - In mice genetically predisposed to glaucoma, vitamin B3 added to drinking water is effective at preventing the disease, a research team led by Jackson Laboratory Professor and Howard Hughes Medical Investigator Simon W.M. John reports in the journal Science.

Glaucoma is one of the most common neurodegenerative diseases, affecting an estimated 80 million people worldwide. In most glaucoma patients, harmfully high pressure inside the eye or intraocular pressure leads to the progressive dysfunction and loss of retinal ganglion cells. Retinal ganglion cells are the neuronal cells that connect the eye to the brain via the optic nerve. Increasing age is a key risk factor for glaucoma, contributing to both harmful elevation of intraocular pressure and increased neuronal vulnerability to pressure-induced damage.

The vitamin administration was surprisingly effective, eliminating the vast majority of age-related molecular changes and providing a remarkably robust protection against glaucoma. It offers promise for developing inexpensive and safe treatments for glaucoma patients.

"We wanted to identify key age-related susceptibility factors that change with age in the eye," John says, "and that therefore increase vulnerability to disease and in particular neuronal disease." By understanding general age-related mechanism, there is the potential to develop new interventions to generally protect from common age-related disease processes in many people. Conducting a variety of genomic, metabolic, neurobiological and other tests in mice susceptible to inherited glaucoma, compared to control mice, the researchers discovered that NAD, a molecule vital to energy metabolism in neurons and other cells, declines with age.

"There's an analogy with an old motorbike," John says. "It runs just fine, but little things get less reliable with age. One day you stress it: you drive it up a steep hill or you go on really long journey and you get in trouble. It's less reliable than a new bike and it's going to fail with a higher frequency than that new bike."

The decrease in NAD levels reduces the reliability of neurons' energy metabolism, especially under stress such as increased intraocular pressure. "Like taking that big hill on your old bike, some things are going to fail more often," John says. "The amount of failure will increase over time, resulting in more damage and disease progression."

In essence, the treatments of vitamin B3 (nicotinamide, an amide form of vitamin B3, also called niacinamide) boosted the metabolic reliability of aging retinal ganglion cells, keeping them healthier for longer. "Because these cells are still healthy, and still metabolically robust," says JAX Postdoctoral Associate Pete Williams, first author of the study, "even when high intraocular pressure turns on, they better resist damaging processes."

The researchers also found that a single gene-therapy application of Nmnat1 (the gene for an enzyme that makes NAD from nicotinamide) prevented glaucoma from developing in this mouse model. "It can be a problem for patients, especially the elderly, to take their drugs every day and in the correct dose," Williams says. "So gene therapy could be a one-shot, protective treatment." He notes that gene therapies, through injections into the eye, have been approved for a handful of very rare, human genetic eye disorders, and their demonstration of an important age-dependent factor may enable gene therapy for more common eye disease.

John says that the team is pursuing clinical partnerships to begin the process of testing the effectiveness of vitamin B3 treatment in glaucoma patients. They are also exploring potential applications for the treatment in other diseases involving neurodegeneration.

Collaborating with the John lab was Vittorio Porciatti of the Bascom Palmer Eye Institute at the University of Miami Miller School of Medicine, and the late Nobel Laureate Oliver Smithies of the University of North Carolina, Chapel Hill.

Funding sources for the research included National Eye Institute grant EY11721, the Barbara and Joseph Cohen Foundation, and National Heart, Lung and Blood Institute grant HL49277. Simon John is an Investigator of the Howard Hughes Medical Institute, and a research assistant professor in the opthalmology department of Tufts University School of Medicine.

The Jackson Laboratory is an independent, nonprofit biomedical research institution based in Bar Harbor, Maine, with a National Cancer Institute-designated Cancer Center, a facility in Sacramento, Calif., and a genomic medicine institute in Farmington, Conn. It employs 1,800 staff, and its mission is to discover precise genomic solutions for disease and empower the global biomedical community in the shared quest to improve human health.

Williams et al.: Vitamin B3 modulates mitochondrial vulnerability and prevents glaucoma in aged mice. Science, February 16, 2017, doi:10.1126/science.aal0092.

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