Efficacy and tolerability of EH301 for amyotrophic lateral sclerosis: a randomized, double-blind, placebo-controlled human pilot study

Rubia, José Enrique de la; Drehmer, Eraci; Platero, José Luis; Benlloch, María; Caplliure-Llopis, Jordi; Villarón-Casales, Carlos; Bernardo, Nieves de; Alarcón, Jorge; Fuente, Cristian de la; Carrera, S.; Sancho, David; García-Pardo, Pilar; Pascual, R. A.; JuÁrez, Marta; Cuerda-Ballester, María; Forner, Alfonso; Castillo, Sandra Sancho; Barrios, Carlos; Obrador, Elena; Marchio, Patricia; Salvador, Rosario; Holmes, Holly; Dellinger, Ryan W.; Guarente, Leonard; Estrela, José M.

doi:10.1080/21678421.2018.1536152

Cited by 76 publications

(53 citation statements)

References 29 publications

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“…In support of our data, it has also been reported that Sirt3 −/− mouse cortical neurons are particularly vulnerable to excitatory, oxidative, and metabolic stress [25]. Our data support recently published work that NAD + levels in ALS patients are reduced compared to the healthy population [26], and confirm that supplementation of NAD + precursors may benefit ALS.…”

Section: Discussionsupporting

confidence: 92%

“…iNAMPT functions as the rate-limiting enzyme of the mammalian NAD + biosynthesis salvage pathway, and depletion of iNAMPT in MNs also led to reduced NAD + levels and increased mitochondrial protein acetylation. While multiple studies have shown that low NAD + levels are associated with ALS [26][27][28], the exact reasons for NAD + decline remain debatable. The balance between NAD + biosynthesis and NAD + degradation determines cellular NAD + bioavailability.…”

Section: Discussionmentioning

confidence: 99%

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ALS motor neurons exhibit hallmark metabolic defects that are rescued by SIRT3 activation

et al. 2020

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Motor neurons (MNs) are highly energetic cells and recent studies suggest that altered energy metabolism precede MN loss in amyotrophic lateral sclerosis (ALS), an age-onset neurodegenerative disease. However, clear mechanistic insights linking altered metabolism and MN death are still missing. In this study, induced pluripotent stem cells from healthy controls, familial ALS, and sporadic ALS patients were differentiated toward spinal MNs, cortical neurons, and cardiomyocytes. Metabolic flux analyses reveal an MN-specific deficiency in mitochondrial respiration in ALS. Intriguingly, all forms of familial and sporadic ALS MNs tested in our study exhibited similar defective metabolic profiles, which were attributed to hyper-acetylation of mitochondrial proteins. In the mitochondria, Sirtuin-3 (SIRT3) functions as a mitochondrial deacetylase to maintain mitochondrial function and integrity. We found that activating SIRT3 using nicotinamide or a small molecule activator reversed the defective metabolic profiles in all our ALS MNs, as well as correct a constellation of ALS-associated phenotypes.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

ALS motor neurons exhibit hallmark metabolic defects that are rescued by SIRT3 activation

et al. 2020

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“…Compared with the placebo control group, EH301 can significantly alleviate the development of ALS. 501,565 NAD + in cardiac and renal diseases NAD + and heart failure (HF). HF is a complex clinical syndrome caused by various initial heart damage and subsequent disturbance in compensatory effects and pathogenesis mechanisms.…”

Section: -Hk 3-hydroxykynureninementioning

confidence: 99%

“…Compared with the placebo control group, EH301 can significantly alleviate the development of ALS. 501 , 565 …”

Section: Abnormal Nad + Metabolism In the Pathophymentioning

confidence: 99%

NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential

Xie

Zhang

Gao

et al. 2020

Sig Transduct Target Ther

551

383

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Nicotinamide adenine dinucleotide (NAD+) and its metabolites function as critical regulators to maintain physiologic processes, enabling the plastic cells to adapt to environmental changes including nutrient perturbation, genotoxic factors, circadian disorder, infection, inflammation and xenobiotics. These effects are mainly achieved by the driving effect of NAD+ on metabolic pathways as enzyme cofactors transferring hydrogen in oxidation-reduction reactions. Besides, multiple NAD+-dependent enzymes are involved in physiology either by post-synthesis chemical modification of DNA, RNA and proteins, or releasing second messenger cyclic ADP-ribose (cADPR) and NAADP+. Prolonged disequilibrium of NAD+ metabolism disturbs the physiological functions, resulting in diseases including metabolic diseases, cancer, aging and neurodegeneration disorder. In this review, we summarize recent advances in our understanding of the molecular mechanisms of NAD+-regulated physiological responses to stresses, the contribution of NAD+ deficiency to various diseases via manipulating cellular communication networks and the potential new avenues for therapeutic intervention.

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“…A recent human pilot study [58], demonstrating that the experimental therapeutic EH301 may be able to slow the progressive decline in functionality, strength and lung function, may offer new insight into the pathophysiology underpinning ALS. EH301 is a combination of nicotinamide riboside (NR) and pterostilbene (PT); compounds that are predicted to increase availability of the coenzyme NAD + and support the activity of the SIRT and their downstream targets.…”

Section: Mitochondria and The Mechanism Of Motor Neuron Deathmentioning

confidence: 99%

Oxidative Stress, Neuroinflammation and Mitochondria in the Pathophysiology of Amyotrophic Lateral Sclerosis

et al. 2020

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Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron (MN) disease. Its primary cause remains elusive, although a combination of different causal factors cannot be ruled out. There is no cure, and prognosis is poor. Most patients with ALS die due to disease-related complications, such as respiratory failure, within three years of diagnosis. While the underlying mechanisms are unclear, different cell types (microglia, astrocytes, macrophages and T cell subsets) appear to play key roles in the pathophysiology of the disease. Neuroinflammation and oxidative stress pave the way leading to neurodegeneration and MN death. ALS-associated mitochondrial dysfunction occurs at different levels, and these organelles are involved in the mechanism of MN death. Molecular and cellular interactions are presented here as a sequential cascade of events. Based on our present knowledge, the discussion leads to the idea that feasible therapeutic strategies should focus in interfering with the pathophysiology of the disease at different steps.

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Efficacy and tolerability of EH301 for amyotrophic lateral sclerosis: a randomized, double-blind, placebo-controlled human pilot study

Cited by 76 publications

References 29 publications

ALS motor neurons exhibit hallmark metabolic defects that are rescued by SIRT3 activation

ALS motor neurons exhibit hallmark metabolic defects that are rescued by SIRT3 activation

NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential

Oxidative Stress, Neuroinflammation and Mitochondria in the Pathophysiology of Amyotrophic Lateral Sclerosis

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