Therapeutic news in ALS

International audienceAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by death of motor neurons in the cortex and the spinal cord. This loss of motor neurons causes progressive weakness and amyotrophy. To date, the median duration of survival in patients with ALS, from first symptoms to death, is estimated to be 36 months. Currently the treatment is limited to two options: riluzole which prolongs survival for a few months and edaravone which is available in only a few countries and also has a small impact on disease progression. There is an urgent need for more effective drugs in this disease to significantly improve progression. Over the last 30 years, all trials have failed to find a curative drug for ALS. This is due, partially, to the heterogeneity of the clinical features and the pathophysiology of motor neuron death. We present in this review the various treatment options currently being developed for ALS, with an emphasis on the range of therapeutic approaches being explored, from old drugs tested in a new indication to innovative drugs obtained via biotechnology or gene therapy

Ferritin and LDL-cholesterol as biomarkers of fat-free mass loss in ALS

International audienceThe availability of longitudinal clinical and biological data led us to wonder whether these parameters could be used to predict disturbances in body composition during ALS progression. Bioelectrical impedance analysis (BIA), as well as clinical and biological parameters (blood lipids and ferritin), were collected one year after diagnosis in ALS patients. The correlations were evaluated by the Spearman test. Performances to predict the evolution of BIA parameters during ALS evolution were evaluated by ROC analysis. Forty-two ALS patients were enrolled. Variations in FFM over one year were correlated to the variations in LDL-cholesterol (r = 0.53, p = 0.002) and ferritin (r = -0.58, p = 0.0002). To predict FFM loss, an increase in ferritin over 9 µg/L had a sensitivity of 90.0% and a specificity of 80.0% (p < 0.0001). Ferritine evolution would allow to easily follow the FFM without BIA during ALS. In addition, an adapted nutritional treatment based on this biological parameter might slow down ALS progression

Some CSF Kynurenine Pathway Intermediates Associated with Disease Evolution in Amyotrophic Lateral Sclerosis

The aim of this study was to evaluate the kynurenine pathway (KP) and amino acids profile, using mass spectrometry, in the cerebrospinal fluid (CSF) of 42 amyotrophic lateral sclerosis (ALS) patients at the diagnosis and 40 controls to detect early disorders of these pathways. Diagnostic and predictive ability (based on weight loss, forced vital capacity, ALS Functional Rating Scale—Revised evolution over 12 months, and survival time) of these metabolites were evaluated using univariate followed by supervised multivariate analysis. The multivariate model between ALS and controls was not significant but highlighted some KP metabolites (kynurenine (KYN), kynurenic acid (KYNA), 3-Hydroxynurenine (3-HK)/KYNA ratio), and amino acids (Lysine, asparagine) as involved in the discrimination between groups (accuracy 62%). It revealed a probable KP impairment toward neurotoxicity in ALS patients and in bulbar forms. Regarding the prognostic effect of metabolites, 12 were commonly discriminant for at least 3 of 4 disease evolution criteria. This investigation was crucial as it did not show significant changes in CSF concentrations of amino acids and KP intermediates in early ALS evolution. However, trends of KP modifications suggest further exploration. The unclear kinetics of neuroinflammation linked to KP support the interest in exploring these pathways during disease evolution through a longitudinal strategy

Metabolic Profile and Pathological Alterations in the Muscle of Patients with Early-Stage Amyotrophic Lateral Sclerosis

Diverse biomarkers and pathological alterations have been found in muscle of patients with Amyotrophic lateral sclerosis (ALS), but the relation between such alterations and dysfunction in energetic metabolism remains to be investigated. We established the metabolome of muscle and serum of ALS patients and correlated these findings with the clinical status and pathological alterations observed in the muscle. We obtained data from 20 controls and 17 ALS patients (disease duration: 9.4 ± 6.8 months). Multivariate metabolomics analysis identified a distinct serum metabolome for ALS compared to controls (p-CV-ANOVA SOD3 (p = 0.0017) and GLRX2(1) (p = 0.0022) in ALS muscle. Analysis of mitochondrial enzymatic activity in muscle revealed higher complex II/CS (p = 0.04) and lower LDH (p = 0.03) activity in ALS than in controls. Our study showed, for the first time, a global dysfunction in the muscle of early-stage ALS patients. Furthermore, we identified novel metabolites to be employed as biomarkers for diagnosis and prognosis of ALS patients