Biomarker Identification, Safety, and Efficacy of High-Dose Antioxidants for Adrenomyeloneuropathy: a Phase II Pilot Study
Por:
Casasnovas C, Ruiz M, Schlüter A, Naudí A, Fourcade S, Veciana M, Castañer S, Albertí A, Bargalló N, Johnson M, Raymond GV, Fatemi A, Moser AB, Villarroya-Gombau F, Portero-Otín M, Artuch-Iriberri R, Pamplona R and Pujol A
Publicada:
1 oct 2019
Ahead of Print:
10 may 2019
Resumen:
X-Adrenoleukodystrophy (X-ALD) and its adult-onset, most prevalent variant adrenomyeloneuropathy (AMN) are caused by mutations in the peroxisomal transporter of the very long-chain fatty acid ABCD1. AMN patients classically present spastic paraparesis that can progress over decades, and a satisfactory treatment is currently lacking. Oxidative stress is an early culprit in X-ALD pathogenesis. A combination of antioxidants halts the clinical progression and axonal damage in a murine model of AMN, providing a strong rationale for clinical translation. In this phase II pilot, open-label study, 13 subjects with AMN were administered a high dose of alpha-tocopherol, N-acetylcysteine, and alpha-lipoic acid in combination. The primary outcome was the validation of a set of biomarkers for monitoring the biological effects of this and future treatments. Functional clinical scales, the 6-minute walk test (6MWT), electrophysiological studies, and cerebral MRI served as secondary outcomes. Most biomarkers of oxidative damage and inflammation were normalized upon treatment, indicating an interlinked redox and inflammatory homeostasis. Two of the inflammatory markers, MCP1 and 15-HETE, were predictive of the response to treatment. We also observed a significant decrease in central motor conduction time, together with an improvement or stabilization of the 6MWT in 8/10 subjects. This study provides a series of biomarkers that are useful to monitor redox and pro-inflammatory target engagement in future trials, together with candidate biomarkers that may serve for patient stratification and disease progression, which merit replication in future clinical trials. Moreover, the clinical results suggest a positive signal for extending these studies to phase III randomized, placebo-controlled, longer-term trials with the actual identified dose. Identifier: NCT01495260
Filiaciones:
Casasnovas C:
Neuromuscular Unit, Neurology Department, Bellvitge University Hospital, Feixa Llarga s/n, 08908, L'Hospitalet de Llobregat, Barcelona, Spain
Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute, Hospital Duran i Reynals, Gran Via de l'Hospitalet 199, 08908, L'Hospitalet de Llobregat, Barcelona, Spain
Center for Biomedical Research on Rare Diseases, Institute of Health Carlos III, Monforte de Lemos 3-5, Pabellón 11, 28029, Madrid, Spain
Ruiz M:
Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute, Hospital Duran i Reynals, Gran Via de l'Hospitalet 199, 08908, L'Hospitalet de Llobregat, Barcelona, Spain
Center for Biomedical Research on Rare Diseases, Institute of Health Carlos III, Monforte de Lemos 3-5, Pabellón 11, 28029, Madrid, Spain
Institute of Neuropathology, Bellvitge Biomedical Research Institute, Gran Via de l'Hospitalet 199, 08908, L'Hospitalet de Llobregat, Barcelona, Spain
Schlüter A:
Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute, Hospital Duran i Reynals, Gran Via de l'Hospitalet 199, 08908, L'Hospitalet de Llobregat, Barcelona, Spain
Center for Biomedical Research on Rare Diseases, Institute of Health Carlos III, Monforte de Lemos 3-5, Pabellón 11, 28029, Madrid, Spain
Institute of Neuropathology, Bellvitge Biomedical Research Institute, Gran Via de l'Hospitalet 199, 08908, L'Hospitalet de Llobregat, Barcelona, Spain
Naudí A:
Biomedical Research Institute of Lleida, Montserrat Roig 2, 25008, Lleida, Spain
Fourcade S:
Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute, Hospital Duran i Reynals, Gran Via de l'Hospitalet 199, 08908, L'Hospitalet de Llobregat, Barcelona, Spain
Center for Biomedical Research on Rare Diseases, Institute of Health Carlos III, Monforte de Lemos 3-5, Pabellón 11, 28029, Madrid, Spain
Institute of Neuropathology, Bellvitge Biomedical Research Institute, Gran Via de l'Hospitalet 199, 08908, L'Hospitalet de Llobregat, Barcelona, Spain
Veciana M:
Neurophysiology Unit, Neurology Department, Hospital Universitari de Bellvitge, Feixa Llarga s/n, 08908, L'Hospitalet de Llobregat, Barcelona, Spain
Castañer S:
Centre Bellvitge, Institut de Diagnòstic per la Imatge, Feixa Llarga s/n, 08908, L'Hospitalet de Llobregat, Barcelona, Spain
Albertí A:
Neuromuscular Unit, Neurology Department, Bellvitge University Hospital, Feixa Llarga s/n, 08908, L'Hospitalet de Llobregat, Barcelona, Spain
Bargalló N:
Department of Neuroradiology, Hospital Clínic, Barcelona, Spain
Magnetic Resonance Imaging Core Facility, Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Johnson M:
Deparment of Neurology and Pediatrics, University of Minnesota Medical Center, 516 Delaware Street Southeast, Minneapolis, Minnesota, 55455, USA
Raymond GV:
Deparment of Neurology and Pediatrics, University of Minnesota Medical Center, 516 Delaware Street Southeast, Minneapolis, Minnesota, 55455, USA
Fatemi A:
Kennedy Krieger Institute, 707 North Broadway, Baltimore, Maryland, 21205, USA
Moser AB:
Kennedy Krieger Institute, 707 North Broadway, Baltimore, Maryland, 21205, USA
Villarroya-Gombau F:
Departament de Bioquimica i Biologia Molecular and Institute of Biomedicine of the University of Barcelona, Facultat de Biologia, Universitat de Barcelona, Avinguda Diagonal 645, 08028, Barcelona, Spain
Center for Biomedical Research in Physiopathology of Obesity and Nutrition, Bellvitge Biomedical Research Institute, Monforte de Lemos 3-5, Pabellón 11, 28029, Madrid, Spain
Portero-Otín M:
Biomedical Research Institute of Lleida, Montserrat Roig 2, 25008, Lleida, Spain
Artuch-Iriberri R:
Center for Biomedical Research on Rare Diseases, Institute of Health Carlos III, Monforte de Lemos 3-5, Pabellón 11, 28029, Madrid, Spain
Institut de Recerca Sant Joan de Déu, Passeig de Sant Joan de Déu 2, 08950, Esplugues de Llobregat, Barcelona, Spain
Pamplona R:
Biomedical Research Institute of Lleida, Montserrat Roig 2, 25008, Lleida, Spain
Pujol A:
Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute, Hospital Duran i Reynals, Gran Via de l'Hospitalet 199, 08908, L'Hospitalet de Llobregat, Barcelona, Spain.
Center for Biomedical Research on Rare Diseases, Institute of Health Carlos III, Monforte de Lemos 3-5, Pabellón 11, 28029, Madrid, Spain.
Institute of Neuropathology, Bellvitge Biomedical Research Institute, Gran Via de l'Hospitalet 199, 08908, L'Hospitalet de Llobregat, Barcelona, Spain.
Catalan Institution of Research and Advanced Studies, Passeig de Lluís Companys 23, 08010, Barcelona, Spain.
Green Submitted, hybrid
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