Nicotinamide shows promise as neuroprotective treatment for glaucoma

Nicotinamide may help overcome the cellular energy crisis that leads to neuronal degeneration.

Dietary supplementation with nicotinamide, a vitamin B-derived coenzyme present in most living cells, might delay or even prevent neurodegeneration in glaucoma.

“Following the positive results of animal laboratory studies, we are moving toward human clinical trials,” Jeffrey M. Liebmann, MD, director of the glaucoma service at Columbia University Medical Center, told Ocular Surgery News.

Protecting retinal ganglion cells (RGCs) and their axons is an important therapeutic goal in glaucoma, hard to achieve and measure but worth pursuing.

“We have plenty of options now to lower IOP, but many patients still progress. Applying neuroprotection to the eye would be a marvelous opportunity, especially if the treatment was oral rather than eye drops because it is easier for elderly patients to take a pill than put a drop in the eye,” he said.

Several agents designed to protect or restore neuronal health in glaucoma have failed in clinical trials. Memantine was tested for glaucoma in two phase 3 trials in 2,000 patients, raising great expectations. However, the study endpoints were not met.

Jeffrey M. Liebmann

“It is difficult to study these drugs because they typically require repetitive visual field and optic nerve structural testing over a long period of time, and determining endpoints is not always easy,” Liebmann said. “However, we now have better ways of measuring treatment efficacy and more advanced technologies for visual field testing and new imaging technologies for assessment of optic nerve structure and function.”

Key factor for energy metabolism

Mitochondrial dysfunction may be at the origin of ganglion cell damage in glaucoma. Nicotinamide adenine dinucleotide (NAD), a key factor for energy metabolism within mitochondria, declines with age and makes RGCs more vulnerable to stress factors such as elevated IOP.

“Several studies looked at mitochondrial abnormalities during the disease, but in our laboratory studies we took a further step, looking at abnormalities that can be detected before any sign of the disease appears. This is how we became interested in NAD and in how the decline of NAD level may lead to an energy crisis and metabolism failure within the mitochondria, leading in turn to RGC damage,”Simon W.M. John, PhD, told OSN. John, who is affiliated with The Jackson Laboratory and Howard Hughes Medical Institute in Bar Harbor, Maine, and Tufts University of Medicine in Boston, has written extensively on the topic of neurodegeneration in glaucoma.

Nicotinamide is a precursor of NAD. In the body, it is naturally converted into NAD by a two enzyme pathway.

“If we supply this natural precursor to try to boost NAD levels, we may rescue mitochondrial efficiency. This is what we found in our laboratory studies. If we give nicotinamide, we overcome a deficiency of NAD, the mitochondria appear healthy, the cells look much healthier, and the disease process stops,” John said.

Nicotinamide may also be active through other pathways. It has documented vasoactive and vasoprotective properties that might address the vasculature dysfunction component of glaucoma, normalizing the blood flow.

“There is one class of molecules named endothelins that are potent vasoconstrictors and are implicated in animal and human glaucoma. Nicotinamide can antagonize the effects of endothelins on blood vessels, allowing them to stay more open. This is another way nicotinamide could provide protection from the disease,” John said.

A third pathway is the impact on calcium channels and calcium signaling, which is also important in axon degeneration and glaucoma.

Large window of opportunity

Nicotinamide shows promise to be an effective neuroprotective agent in human glaucoma, according to John.

“If we look at the results of our preclinical studies, it was extremely effective as a prophylactic before IOP becomes elevated, but it was also protective after IOP was already elevated. It could be protective at different stages,” he said.

In human glaucoma, retinal ganglion cells die relatively slowly, over a long period of time. Nicotinamide makes nerve cells more resilient and more robust against stressors. Under the stress of high IOP, an eye in which the NAD level is low is likely to have rapid progression of disease. Nicotinamide supplementation normalizes cellular metabolism, strengthening the cells.

“There is a large window of opportunity, since the human disease occurs over decades, to protect many of those cells in the eye. We cannot argue that nicotinamide will revive dead cells, but it boosts cells that are still viable. It makes them more resilient, like younger cells. By analogy, with a brand-new motorbike you can go climbing the Alps, but an older bike can make it only if it is properly reconditioned,” John said.

Toward human trials

Now that the scientific rationale is set, it is time to test nicotinamide for glaucoma in human trials.

“There is strong enough scientific rationale to support the development of a human clinical trial to help determine if nicotinamide may help slow the progression of glaucoma,” Liebmann said.

A human clinical trial is currently under development. In these important preliminary stages, the best source of nicotinamide needs to be identified and the proper dosage established.

“We are going to perform a short-term study to demonstrate tolerability and then we’ll go on to demonstrating the neuroprotective effects of nicotinamide vs. placebo. We have the technology to do it within a reasonable follow-up time,” Liebmann said.

Currently, nicotinamide can be bought “off the shelf,” but both Liebmann and John warned of the dangers of using it in absence of proper indication-specific dosage and dosing schedules. In addition, nutritional supplements are not always up to the best standard of production, they said.

“When we do these trials, one of the important goals is to have a reliable source of these molecules so that we can be sure that they are very safe. It might be a nutraceutical, but it must be formulated on the basis of clinical trial results. The sourcing is important, and I caution people to be careful of what is available today,” John said.

Neuroprotection, the “holy grail” of glaucoma treatment, is certainly going to be achieved; the question is how and when, according to Liebmann.

“There is a large unmet need and potential market for neuroprotection, and this should encourage companies to be more active in the space,” he said. – by Michela Cimberle

Disclosures: John reports no relevant financial disclosures. Liebmann reports he is a consultant to Aerie Pharmaceuticals, Alcon, Allergan, Bausch + Lomb, Carl Zeiss Meditec, Diopsys, Heidelberg Engineering, Inotek Pharmaceuticals, Quark Pharmaceuticals, Reichert, Solx and Sustained Nanosystems.

Dietary supplementation with nicotinamide, a vitamin B-derived coenzyme present in most living cells, might delay or even prevent neurodegeneration in glaucoma.

“Following the positive results of animal laboratory studies, we are moving toward human clinical trials,” Jeffrey M. Liebmann, MD, director of the glaucoma service at Columbia University Medical Center, told Ocular Surgery News.

Protecting retinal ganglion cells (RGCs) and their axons is an important therapeutic goal in glaucoma, hard to achieve and measure but worth pursuing.

“We have plenty of options now to lower IOP, but many patients still progress. Applying neuroprotection to the eye would be a marvelous opportunity, especially if the treatment was oral rather than eye drops because it is easier for elderly patients to take a pill than put a drop in the eye,” he said.

Several agents designed to protect or restore neuronal health in glaucoma have failed in clinical trials. Memantine was tested for glaucoma in two phase 3 trials in 2,000 patients, raising great expectations. However, the study endpoints were not met.

Jeffrey M. Liebmann

“It is difficult to study these drugs because they typically require repetitive visual field and optic nerve structural testing over a long period of time, and determining endpoints is not always easy,” Liebmann said. “However, we now have better ways of measuring treatment efficacy and more advanced technologies for visual field testing and new imaging technologies for assessment of optic nerve structure and function.”

Key factor for energy metabolism

Mitochondrial dysfunction may be at the origin of ganglion cell damage in glaucoma. Nicotinamide adenine dinucleotide (NAD), a key factor for energy metabolism within mitochondria, declines with age and makes RGCs more vulnerable to stress factors such as elevated IOP.

“Several studies looked at mitochondrial abnormalities during the disease, but in our laboratory studies we took a further step, looking at abnormalities that can be detected before any sign of the disease appears. This is how we became interested in NAD and in how the decline of NAD level may lead to an energy crisis and metabolism failure within the mitochondria, leading in turn to RGC damage,”Simon W.M. John, PhD, told OSN. John, who is affiliated with The Jackson Laboratory and Howard Hughes Medical Institute in Bar Harbor, Maine, and Tufts University of Medicine in Boston, has written extensively on the topic of neurodegeneration in glaucoma.

Nicotinamide is a precursor of NAD. In the body, it is naturally converted into NAD by a two enzyme pathway.

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“If we supply this natural precursor to try to boost NAD levels, we may rescue mitochondrial efficiency. This is what we found in our laboratory studies. If we give nicotinamide, we overcome a deficiency of NAD, the mitochondria appear healthy, the cells look much healthier, and the disease process stops,” John said.

Nicotinamide may also be active through other pathways. It has documented vasoactive and vasoprotective properties that might address the vasculature dysfunction component of glaucoma, normalizing the blood flow.

“There is one class of molecules named endothelins that are potent vasoconstrictors and are implicated in animal and human glaucoma. Nicotinamide can antagonize the effects of endothelins on blood vessels, allowing them to stay more open. This is another way nicotinamide could provide protection from the disease,” John said.

A third pathway is the impact on calcium channels and calcium signaling, which is also important in axon degeneration and glaucoma.

Large window of opportunity

Nicotinamide shows promise to be an effective neuroprotective agent in human glaucoma, according to John.

“If we look at the results of our preclinical studies, it was extremely effective as a prophylactic before IOP becomes elevated, but it was also protective after IOP was already elevated. It could be protective at different stages,” he said.

In human glaucoma, retinal ganglion cells die relatively slowly, over a long period of time. Nicotinamide makes nerve cells more resilient and more robust against stressors. Under the stress of high IOP, an eye in which the NAD level is low is likely to have rapid progression of disease. Nicotinamide supplementation normalizes cellular metabolism, strengthening the cells.

“There is a large window of opportunity, since the human disease occurs over decades, to protect many of those cells in the eye. We cannot argue that nicotinamide will revive dead cells, but it boosts cells that are still viable. It makes them more resilient, like younger cells. By analogy, with a brand-new motorbike you can go climbing the Alps, but an older bike can make it only if it is properly reconditioned,” John said.

Toward human trials

Now that the scientific rationale is set, it is time to test nicotinamide for glaucoma in human trials.

“There is strong enough scientific rationale to support the development of a human clinical trial to help determine if nicotinamide may help slow the progression of glaucoma,” Liebmann said.

A human clinical trial is currently under development. In these important preliminary stages, the best source of nicotinamide needs to be identified and the proper dosage established.

PAGE BREAK

“We are going to perform a short-term study to demonstrate tolerability and then we’ll go on to demonstrating the neuroprotective effects of nicotinamide vs. placebo. We have the technology to do it within a reasonable follow-up time,” Liebmann said.

Currently, nicotinamide can be bought “off the shelf,” but both Liebmann and John warned of the dangers of using it in absence of proper indication-specific dosage and dosing schedules. In addition, nutritional supplements are not always up to the best standard of production, they said.

“When we do these trials, one of the important goals is to have a reliable source of these molecules so that we can be sure that they are very safe. It might be a nutraceutical, but it must be formulated on the basis of clinical trial results. The sourcing is important, and I caution people to be careful of what is available today,” John said.

Neuroprotection, the “holy grail” of glaucoma treatment, is certainly going to be achieved; the question is how and when, according to Liebmann.

“There is a large unmet need and potential market for neuroprotection, and this should encourage companies to be more active in the space,” he said. – by Michela Cimberle

Disclosures: John reports no relevant financial disclosures. Liebmann reports he is a consultant to Aerie Pharmaceuticals, Alcon, Allergan, Bausch + Lomb, Carl Zeiss Meditec, Diopsys, Heidelberg Engineering, Inotek Pharmaceuticals, Quark Pharmaceuticals, Reichert, Solx and Sustained Nanosystems.