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Title: Biomarker Identification, Safety, and Efficacy of High-Dose Antioxidants for Adrenomyeloneuropathy: a Phase II Pilot Study
Author: Casasnovas Pons, Carlos
Ruiz, Montserrat
Schlüter, Agatha
Naudi, Alba
Fourcade, Stéphane
Veciana, Misericordia
Castañer, Sara
Albertí, Antonia
Bargalló Alabart, Núria​
Johnson, Maria
Raymond, Gerald V.
Fatemi, Ali
Moser, Ann B.
Villarroya i Gombau, Francesc
Portero-Otín, Manuel
Artuch Iriberri, Rafael
Pamplona, Reinald
Pujol, Aurora
Keywords: Antioxidants
Marcadors bioquímics
Biochemical markers
Issue Date: 1-Oct-2019
Publisher: Springer Verlag
Abstract: 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 α-tocopherol, N-acetylcysteine, and α-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.
Note: Versió postprint del document publicat a:
It is part of: Neurotherapeutics, 2019, vol. 4, p. 1167-1182
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ISSN: 1933-7213
Appears in Collections:Articles publicats en revistes (Bioquímica i Biomedicina Molecular)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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