Biomarker Identification, Safety, and Efficacy of High-Dose Antioxidants for Adrenomyeloneuropathy: a Phase II Pilot Study

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 satisfacto...

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Autores: 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-Otin, Manuel, Artuch Iriberri, Rafael, Pamplona, Reinald, Pujol, Aurora, 1968-
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2019
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/171896
Acceso en línea:https://hdl.handle.net/2445/171896
Access Level:acceso abierto
Palabra clave:Antioxidants
Marcadors bioquímics
Inflamació
Biochemical markers
Inflammation
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spelling Biomarker Identification, Safety, and Efficacy of High-Dose Antioxidants for Adrenomyeloneuropathy: a Phase II Pilot StudyCasasnovas Pons, CarlosRuiz, MontserratSchlüter, AgathaNaudi, AlbaFourcade, StéphaneVeciana, MisericordiaCastañer, SaraAlbertí, AntoniaBargalló Alabart, NúriaJohnson, MariaRaymond, Gerald V.Fatemi, AliMoser, Ann B.Villarroya i Gombau, FrancescPortero-Otin, ManuelArtuch Iriberri, RafaelPamplona, ReinaldPujol, Aurora, 1968-AntioxidantsMarcadors bioquímicsInflamacióAntioxidantsBiochemical markersInflammationX-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. ClinicalTrials.gov Identifier: NCT01495260.Springer Verlag2020202020192020info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersion16 p.application/pdfhttps://hdl.handle.net/2445/171896Articles publicats en revistes (Bioquímica i Biomedicina Molecular)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésVersió postprint del document publicat a: https://doi.org/10.1007/s13311-019-00735-2Neurotherapeutics, 2019, vol. 4, p. 1167-1182https://doi.org/10.1007/s13311-019-00735-2info:eu-repo/grantAgreement/EC/FP7/241622(c) American Society for Experimental NeuroTherapeutics, 2019info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1718962026-05-29T05:05:01Z
dc.title.none.fl_str_mv Biomarker Identification, Safety, and Efficacy of High-Dose Antioxidants for Adrenomyeloneuropathy: a Phase II Pilot Study
title Biomarker Identification, Safety, and Efficacy of High-Dose Antioxidants for Adrenomyeloneuropathy: a Phase II Pilot Study
spellingShingle Biomarker Identification, Safety, and Efficacy of High-Dose Antioxidants for Adrenomyeloneuropathy: a Phase II Pilot Study
Casasnovas Pons, Carlos
Antioxidants
Marcadors bioquímics
Inflamació
Antioxidants
Biochemical markers
Inflammation
title_short Biomarker Identification, Safety, and Efficacy of High-Dose Antioxidants for Adrenomyeloneuropathy: a Phase II Pilot Study
title_full Biomarker Identification, Safety, and Efficacy of High-Dose Antioxidants for Adrenomyeloneuropathy: a Phase II Pilot Study
title_fullStr Biomarker Identification, Safety, and Efficacy of High-Dose Antioxidants for Adrenomyeloneuropathy: a Phase II Pilot Study
title_full_unstemmed Biomarker Identification, Safety, and Efficacy of High-Dose Antioxidants for Adrenomyeloneuropathy: a Phase II Pilot Study
title_sort Biomarker Identification, Safety, and Efficacy of High-Dose Antioxidants for Adrenomyeloneuropathy: a Phase II Pilot Study
dc.creator.none.fl_str_mv 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-Otin, Manuel
Artuch Iriberri, Rafael
Pamplona, Reinald
Pujol, Aurora, 1968-
author Casasnovas Pons, Carlos
author_facet 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-Otin, Manuel
Artuch Iriberri, Rafael
Pamplona, Reinald
Pujol, Aurora, 1968-
author_role author
author2 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-Otin, Manuel
Artuch Iriberri, Rafael
Pamplona, Reinald
Pujol, Aurora, 1968-
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Antioxidants
Marcadors bioquímics
Inflamació
Antioxidants
Biochemical markers
Inflammation
topic Antioxidants
Marcadors bioquímics
Inflamació
Antioxidants
Biochemical markers
Inflammation
description 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. ClinicalTrials.gov Identifier: NCT01495260.
publishDate 2019
dc.date.none.fl_str_mv 2019
2020
2020
2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/171896
url https://hdl.handle.net/2445/171896
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Versió postprint del document publicat a: https://doi.org/10.1007/s13311-019-00735-2
Neurotherapeutics, 2019, vol. 4, p. 1167-1182
https://doi.org/10.1007/s13311-019-00735-2
info:eu-repo/grantAgreement/EC/FP7/241622
dc.rights.none.fl_str_mv (c) American Society for Experimental NeuroTherapeutics, 2019
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) American Society for Experimental NeuroTherapeutics, 2019
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 16 p.
application/pdf
dc.publisher.none.fl_str_mv Springer Verlag
publisher.none.fl_str_mv Springer Verlag
dc.source.none.fl_str_mv Articles publicats en revistes (Bioquímica i Biomedicina Molecular)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812455

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