ILB® Attenuates Clinical Symptoms and Serum Biomarkers of Oxidative/Nitrosative Stress and Mitochondrial Dysfunction in Patients with Amyotrophic Lateral Sclerosis

Giacomo Lazzarino, Renata Mangione, Antonio Belli, Valentina Di Pietro, Zsuzsanna Nagy, Nicholas M Barnes, Lars Bruce, Bernardo M Ropero, Lennart I Persson, Benedetta Manca, Miriam Wissam Saab, Angela M Amorini, Barbara Tavazzi, Giuseppe Lazzarino, Ann Logan, Giacomo Lazzarino, Renata Mangione, Antonio Belli, Valentina Di Pietro, Zsuzsanna Nagy, Nicholas M Barnes, Lars Bruce, Bernardo M Ropero, Lennart I Persson, Benedetta Manca, Miriam Wissam Saab, Angela M Amorini, Barbara Tavazzi, Giuseppe Lazzarino, Ann Logan

Abstract

Oxidative/nitrosative stress and mitochondrial dysfunction is a hallmark of amyotrophic lateral sclerosis (ALS), an invariably fatal progressive neurodegenerative disease. Here, as an exploratory arm of a phase II clinical trial (EudraCT Number 2017-005065-47), we used high performance liquid chromatography(HPLC) to investigate changes in the metabolic profiles of serum from ALS patients treated weekly for 4 weeks with a repeated sub-cutaneous dose of 1 mg/kg of a proprietary low molecular weight dextran sulphate, called ILB®. A significant normalization of the serum levels of several key metabolites was observed over the treatment period, including N-acetylaspartate (NAA), oxypurines, biomarkers of oxidative/nitrosative stress and antioxidants. An improved serum metabolic profile was accompanied by significant amelioration of the patients' clinical conditions, indicating a response to ILB® treatment that appears to be mediated by improvement of tissue bioenergetics, decrease of oxidative/nitrosative stress and attenuation of (neuro)inflammatory processes.

Keywords: HPLC; N-acetylaspartate; amino acids; amyotrophic lateral sclerosis; antioxidants; energy metabolism; low molecular weight-dextran sulphate; mitochondrial dysfunction; oxidative/nitrosative stress; serum biomarkers.

Conflict of interest statement

Patents pertaining to this LMW-DS drug have been filed by Tikomed AB. L.B. is co-inventor of the LMW-DS used in the study and is a board member of Tikomed AB. A.L., Z.N., N.M.B. and A.B. declare consultancy payments from Tikomed AB and/or Neuregenix Ltd. for related services outside the submitted work. The other authors declare that they have no competing interests. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Box plots reporting minimum, maximum, median, 25% and 75% percentiles of the serum concentrations of the neuronal specific metabolite N-acetylaspartate (NAA, (a)) and of indices of energy metabolism impairment (uric acid, (b) and sum of oxypurines (c)) in 13 patients with ALS before (Pre) and after (Post) ILB® treatment. The values found in a group of 163 healthy controls are also reported. (○): open circles are the values of metabolites in each subject enrolled in the study. Means ± S.D. of NAA in controls, patients with ALS before (Pre) and after (Post) ILB® treatment were, respectively, 0.037 ± 0.026, 0.223 ± 0.136 and 0.130 ± 0.084 μmol/L serum. Means ± S.D. of uric acid in controls, patients with ALS before (Pre) and after (Post) ILB® treatment were, respectively, 270.50 ± 57.90, 397.10 ± 70.32 and 371.40 ± 71.98 μmol/L serum. Means ± S.D. of sum of oxypurines in controls, patients with ALS before (Pre) and after (Post) ILB® treatment were, respectively, 276.80 ± 58.45, 407.60 ± 69.34 and 381.20 ± 72.38 μmol/L serum. * Significantly different from Controls, p < 0.001. ** Significantly different from Pre, p < 0.05.
Figure 2
Figure 2
Box plots reporting minimum, maximum, median, 25% and 75% percentiles of the serum concentrations of lipid peroxidation end product (MDA, (a)) and stable compounds of nitric oxide metabolism (nitrite + nitrate, (b)) in 13 patients with ALS before (Pre) and after (Post) ILB® treatment. The values measured in a group of 163 healthy controls are also reported. (○) Open circles are the values of metabolites in each subject enrolled in the study. Means ± S.D. of MDA in controls, patients with ALS before (Pre) and after (Post) ILB® treatment were, respectively, 0.066 ± 0.048, 0.190 ± 0.114 and 0.128 ± 0.046 μmol/L serum. Means ± S.D. of nitrite + nitrate in controls, patients with ALS before (Pre) and after (Post) ILB® treatment were, respectively, 30.90 ± 9.67, 53.98 ± 12.55 and 48.47 ± 12.25 μmol/L serum. * Significantly different from Controls, p < 0.001. ** Significantly different from Pre, p < 0.05.
Figure 3
Figure 3
Box plots reporting minimum, maximum, median, 25% and 75% percentiles of the serum concentrations of amino acids related to muscular protein degradation (ALA, (a)) and to nitric oxide generation (CITR, (b) and ORN/CITR ratio, (c)) in patients with ALS before (Pre) and after (Post) ILB® treatment. The values measured in a group of 163 healthy controls are also reported. (○) Open circles are the values of metabolites in each subject enrolled in the study. Means ± S.D. of ALA in controls, patients with ALS before (Pre) and after (Post) ILB® treatment were, respectively, 364.40 ± 95.50, 429.00 ± 85.96 and 374.70 ± 83.43 μmol/L serum. Means ± S.D. of CITR in controls, patients with ALS before (Pre) and after (Post) ILB® treatment were, respectively, 18.82 ± 4.22, 23.59 ± 7.03 and 18.60 ± 5.10 μmol/L serum. Means ± S.D. of ORN/CITR in controls, patients with ALS before (Pre) and after (Post) ILB® treatment were, respectively, 4.47 ± 1.78, 1.52 ± 0.68 and 2−19 ± 1.03. * Significantly different from Controls, p < 0.001. ** Significantly different from Pre, p < 0.05.
Figure 4
Figure 4
Box plots reporting minimum, maximum, median, 25% and 75% percentiles of the serum concentrations of the main vitamin E congeners (α-tocopherol, (a) and γ-tocopherol, (b)) in patients with ALS before (Pre) and after (Post) ILB® treatment. The values measured in a group of 163 healthy controls are also reported. (○) Open circles are the values of metabolites in each subject enrolled in the study. Means ± S.D. of α-tocopherol in controls, patients with ALS before (Pre) and after (Post) ILB® treatment were, respectively, 25.03 ± 5.78, 9.35 ± 5.54 and 11.70 ± 8.50 μmol/L serum. Means ± S.D. of γ-tocopherol in controls, patients with ALS before (Pre) and after (Post) ILB® treatment were, respectively, 1.05 ± 0.28, 0.497 ± 0.139 and 0.692 ± 0.367 μmol/L serum. * Significantly different from Controls, p < 0.001. ** Significantly different from Pre, p < 0.05.

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