VITALITY-ALS, a phase III trial of tirasemtiv, a selective fast skeletal muscle troponin activator, as a potential treatment for patients with amyotrophic lateral sclerosis: study design and baseline characteristics

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that leads to progressive degeneration of motor neurons (MNs) and severe muscle atrophy without effective treatment. Most research on ALS has been focused on the study of MNs and supporting cells of the central nervous system. Strikingly, the recent observations of pathological changes in muscle occurring before disease onset and independent from MN degeneration have bolstered the interest for the study of muscle tissue as a potential target for delivery of therapies for ALS. Skeletal muscle has just been described as a tissue with an important secretory function that is toxic to MNs in the context of ALS. Moreover, a fine-tuning balance between biosynthetic and atrophic pathways is necessary to induce myogenesis for muscle tissue repair. Compromising this response due to primary metabolic abnormalities in the muscle could trigger defective muscle regeneration and neuromuscular junction restoration, with deleterious consequences for MNs and thereby hastening the development of ALS. However, it remains puzzling how backward signaling from the muscle could impinge on MN death. This review provides a comprehensive analysis on the current state-of-the-art of the role of the skeletal muscle in ALS, highlighting its contribution to the neurodegeneration in ALS through backward-signaling processes as a newly uncovered mechanism for a peripheral etiopathogenesis of the disease.

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Skeletal Muscle Metabolism: Origin or Prognostic Factor for Amyotrophic Lateral Sclerosis (ALS) Development?

Cells ◽

10.3390/cells10061449 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1449

Author(s):

Cyril Quessada ◽

Alexandra Bouscary ◽

Frédérique René ◽

Cristiana Valle ◽

Alberto Ferri ◽

...

Keyword(s):

Skeletal Muscle ◽

Amyotrophic Lateral Sclerosis ◽

Motor Neuron ◽

Motor Neurons ◽

Muscle Metabolism ◽

The Body ◽

Energy Deficit ◽

Acid Oxidation ◽

Progression Of Disease ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive and selective loss of motor neurons, amyotrophy and skeletal muscle paralysis usually leading to death due to respiratory failure. While generally considered an intrinsic motor neuron disease, data obtained in recent years, including our own, suggest that motor neuron protection is not sufficient to counter the disease. The dismantling of the neuromuscular junction is closely linked to chronic energy deficit found throughout the body. Metabolic (hypermetabolism and dyslipidemia) and mitochondrial alterations described in patients and murine models of ALS are associated with the development and progression of disease pathology and they appear long before motor neurons die. It is clear that these metabolic changes participate in the pathology of the disease. In this review, we summarize these changes seen throughout the course of the disease, and the subsequent impact of glucose–fatty acid oxidation imbalance on disease progression. We also highlight studies that show that correcting this loss of metabolic flexibility should now be considered a major goal for the treatment of ALS.

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TDP-43 in skeletal muscle of patients affected with amyotrophic lateral sclerosis

Amyotrophic Lateral Sclerosis ◽

10.3109/17482960902810890 ◽

2010 ◽

Vol 11 (1-2) ◽

pp. 240-243 ◽

Cited By ~ 8

Author(s):

Gianni Sorarú ◽

Valeria Orsetti ◽

Emanuele Buratti ◽

Francisco Baralle ◽

Valentina Cima ◽

...

Keyword(s):

Skeletal Muscle ◽

Amyotrophic Lateral Sclerosis ◽

Lateral Sclerosis

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Protein misfolding, amyotrophic lateral sclerosis and guanabenz: protocol for a phase II RCT with futility design (ProMISe trial)

BMJ Open ◽

10.1136/bmjopen-2016-015434 ◽

2017 ◽

Vol 7 (8) ◽

pp. e015434 ◽

Cited By ~ 5

Author(s):

Eleonora Dalla Bella ◽

Irene Tramacere ◽

Giovanni Antonini ◽

Giuseppe Borghero ◽

Margherita Capasso ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Amyotrophic Lateral Sclerosis ◽

Placebo Group ◽

Phase Ii ◽

Critical Role ◽

Protein Translation ◽

Phase Iii ◽

Protein Accumulation ◽

Neuroprotective Effects ◽

Lateral Sclerosis

IntroductionRecent studies suggest that endoplasmic reticulum stress may play a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS) through an altered regulation of the proteostasis, the cellular pathway-balancing protein synthesis and degradation. A key mechanism is thought to be the dephosphorylation of eIF2α, a factor involved in the initiation of protein translation. Guanabenz is an alpha-2-adrenergic receptor agonist safely used in past to treat mild hypertension and is now an orphan drug. A pharmacological action recently discovered is its ability to modulate the synthesis of proteins by the activation of translational factors preventing misfolded protein accumulation and endoplasmic reticulum overload. Guanabenz proved to rescue motoneurons from misfolding protein stress both in in vitro and in vivo ALS models, making it a potential disease-modifying drug in patients. It is conceivable investigating whether its neuroprotective effects based on the inhibition of eIF2α dephosphorylation can change the progression of ALS.Methods and analysesProtocolised Management In Sepsis is a multicentre, randomised, double-blind, placebo-controlled phase II clinical trial with futility design. We will investigate clinical outcomes, safety, tolerability and biomarkers of neurodegeneration in patients with ALS treated with guanabenz or riluzole alone for 6 months. The primary aim is to test if guanabenz can reduce the proportion of patients progressed to a higher stage of disease at 6 months compared with their baseline stage as measured by the ALS Milano-Torino Staging (ALS-MITOS) system and to the placebo group. Secondary aims are safety, tolerability and change in at least one biomarker of neurodegeneration in the guanabenz arm compared with the placebo group. Findings will provide reliable data on the likelihood that guanabenz can slow the course of ALS in a phase III trial.Ethics and disseminationThe study protocol was approved by the Ethics Committee of IRCCS ‘Carlo Besta Foundation’ of Milan (Eudract no. 2014-005367-32 Pre-results) based on the Helsinki declaration.

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AN AYURVEDIC CASE REPORT ON AMYOTROPHIC LATERAL SCLEROSIS

November 2020 - International Ayurvedic Medical Journal ◽

10.46607/iamj4409112021 ◽

2021 ◽

Vol 9 (11) ◽

pp. 2903-2908

Author(s):

Ambika. K ◽

Arundhathi. K ◽

Lekshmi G. Krishna

Keyword(s):

Quality Of Life ◽

Skeletal Muscle ◽

Amyotrophic Lateral Sclerosis ◽

Case Report ◽

Lower Limbs ◽

Skeletal Muscle Weakness ◽

Treatment Principle ◽

Severe Type ◽

Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a common and most severe type of Motor Neuron Disease. It is characterized by progressive skeletal muscle weakness, wasting and fasciculations. Survival is for 3-5 years, and the death is from respiratory paralysis. The incidence of ALS is between 0.6 and 3.8 per 100000 persons per year. Males are predominantly affected. Here is a case report of 45yrs old male who presented with complaints of difficulty in walking since 3years, with an insidious asymmetric onset of weakness of bilateral lower limbs with wasting and fasciculations. In Ayurveda, the case was symptomatologically diagnosed as Mamsa Sosha, which occurs as the result of obstruction of Snayu and Rakthadhamanis (Mamsavaha srotomoolas). The assessment was done using ALSFRS-R Scale. The treatment was aimed at improving the quality of life and also decreasing the rate of disease progression. The treatment principle adopted was Srothosodhana (Ama- Avaranaghna cikitsa) and Brimhana. Promising results were obtained after treatment. Keywords: ALS, MND, Ayurveda, Avaranaghna cikitsa, Mamsa Sosha, Mamsa Kshaya

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