The challenge of treating ALS
Amyotrophic lateral sclerosis (ALS), also known as “Lou Gehrig’s disease”, is a devastating neurodegenerative disease that affects nearly half a million people worldwide, the majority of whom are over 50.
ALS damages motor neurons (nerve cells) in the brain and spinal cord that control muscles, resulting in progressive muscle weakness, and eventually paralysis and death (McCombe et al., 2020). Most people with ALS die within 3 years of first showing signs of the disease, so effective treatments are desperately needed.
Unfortunately, the only two drugs currently approved for treating ALS — riluzol and edaravone — merely slow its progression. Patients and their families urgently need a treatment that can halt or even reverse the devastating effects of the disease.
Targeting the cellular causes of ALS
Thankfully, scientific research into the causes of ALS at the cellular level is revealing new avenues for hope. In particular, maintaining levels of nicotinamide dinucelotide (NAD+) in motor neurons could be key to preventing neuronal damage and progressive muscle weakness (Obrador et al., 2021).
NAD+ is a coenzyme (helper molecule) found naturally in the body that supports healthy energy production, DNA repair, and cell survival. In ALS, NAD+ levels become depleted in the energy-demanding motor neurons as the cells are put under high levels of “oxidative stress”.
Oxidative stress is a toxic cellular state caused by an excess of oxidants, which are generated by tissue inflammation and dysfunctional energy production (Lyon et al., 2019). NAD+ helps to prevent oxidative damage to motor neurons via two types of enzymes (active proteins) — sirtuins and PARPs (Amjad et al., 2021).
Sirtuins fight oxidative stress and increase cell survival by regulating inflammation and energy production, and by promoting antioxidant defenses. Along with PARPs, they also repair damage to DNA caused by the toxic oxidants.
Crucially, both sirtuins and PARPs consume cellular NAD+ stores, meaning that maintaining NAD+ levels is essential to preventing the oxidative stress that leads to devastating motor neuron damage in ALS.
Raising NAD+ levels in the body
How can NAD+ levels be raised to help treat ALS? Luckily, there are a number of scientifically proven ways to increase cellular NAD+ stores that are suitable for people with ALS.
One approach is to take daily or twice daily supplements to deliver NAD+ to the motor neurons. The most commonly used and effective supplements are nicotinamide riboside (NR) (Martens et al., 2018) and nicotinamide mononucleotide (NMN) (Irie et al., 2020; Yoshino et al., 2021). These precursor forms of NAD+ are metabolized in the body to produce bioavailable NAD+.
Another effective approach is to deliver NAD+ directly into the body via intravenous injection. This maximizes the amount of bioavailable NAD+ within a short timeframe.
Treating ALS using NAD+ and antioxidants
Clinical trials are beginning to show exciting evidence that taking NAD+ supplements in combination with antioxidants has significant positive effects on ALS. Unlike existing treatments, this treatment combination might not only slow the damage caused by ALS, but actually reverse it over time.
The research conducted so far has focused on combining NR supplements for NAD+ with pterostilbene (PT), a natural antioxidant found in blueberries (Dellinger et al., 2017).
In a breakthrough phase 1 clinical trial conducted in 2019 by Elysium Health, 32 people with ALS were treated using NR and PT (de la Rubia et al., 2019). Astonishingly, after receiving the treatment daily for 4 months, the participants showed reduced symptoms of ALS and better lung and muscle function. Meanwhile, those receiving the ineffective placebo treatment showed worse ALS symptoms and function, as expected.
Hope for the future treatment of ALS
These exciting results suggest that it might be possible to reverse the damaging effects of ALS by increasing NAD+ and antioxidant levels in the body.
All eyes are now on the follow-up phase 2 trial currently being conducted by Elysium Health. This trial aims to confirm the benefits of a daily dose of up to 1,500 mg NR and 300 mg PT in a much larger group of several hundred ALS patients.
Thanks to in-depth scientific research, scientists and clinicians are making real progress in developing treatments for ALS. Therapies that increase NAD+ and antioxidant levels are offering hope to ALS patients and their families that the function and quality of life lost to this devastating disease might one day be regained.
References
Amjad, S., Nisar, S., Bhat, A. A., Frenneaux, M. P., Fakhro, K., Haris, M., … & Bagga, P. (2021). Role of NAD+ in regulating cellular and metabolic signaling pathways. Molecular Metabolism, 101195. https://doi.org/10.1016/j.molmet.2021.101195
de la Rubia, J. E., Drehmer, E., Platero, J. L., Benlloch, M., Caplliure-Llopis, J., Villaron-Casales, C., … & Estrela, J. M. (2019). Efficacy and tolerability of EH301 for amyotrophic lateral sclerosis: a randomized, double-blind, placebo-controlled human pilot study. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 20(1-2), 115-122. https://doi.org/10.1080/21678421.2018.1536152
Dellinger, R. W., Santos, S. R., Morris, M., Evans, M., Alminana, D., Guarente, L., & Marcotulli, E. (2017). Repeat dose NRPT (nicotinamide riboside and pterostilbene) increases NAD+ levels in humans safely and sustainably: a randomized, double-blind, placebo-controlled study. NPJ Aging and Mechanisms of Disease, 3, 17. https://doi.org/10.1038/s41514-017-0016-9
Irie, J., Inagaki, E., Fujita, M., Nakaya, H., Mitsuishi, M., Yamaguchi, S., … & Itoh, H. (2020). Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men. Endocrine Journal, 67(2), 153-160. https://doi.org/10.1507/endocrj.EJ19-0313
Lyon, M. S., Wosiski‐Kuhn, M., Gillespie, R., Caress, J., & Milligan, C. (2019). Inflammation, Immunity, and amyotrophic lateral sclerosis: I. Etiology and pathology. Muscle & Nerve, 59(1), 10-22. https://doi.org/10.1002/mus.26289
Martens, C. R., Denman, B. A., Mazzo, M. R., Armstrong, M. L., Reisdorph, N., McQueen, M. B., Chonchol, M., & Seals, D. R. (2018). Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nature Communications, 9(1), 1286. https://doi.org/10.1038/s41467-018-03421-7
McCombe, P. A., Garton, F. C., Katz, M., Wray, N. R., & Henderson, R. D. (2020). What do we know about the variability in survival of patients with amyotrophic lateral sclerosis?. Expert Review of Neurotherapeutics, 20(9), 921-941. https://doi.org/10.1080/14737175.2020.1785873
Obrador, E., Salvador-Palmer, R., López-Blanch, R., Dellinger, R. W., & Estrela, J. M. (2021). NAD+ Precursors and Antioxidants for the Treatment of Amyotrophic Lateral Sclerosis. Biomedicines, 9(8), 1000. https://doi.org/10.3390/biomedicines9081000
Yoshino, M., Yoshino, J., Kayser, B. D., Patti, G. J., Franczyk, M. P., Mills, K. F., … & Klein, S. (2021). Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science, 372(6547), 1224-1229. https://doi.org/10.1126/science.abe9985