TY - JOUR
T1 - Biomarker Identification, Safety, and Efficacy of High-Dose Antioxidants for Adrenomyeloneuropathy
T2 - a Phase II Pilot Study
AU - Casasnovas, Carlos
AU - Ruiz, Montserrat
AU - Schlüter, Agatha
AU - Naudí, Alba
AU - Fourcade, Stéphane
AU - Veciana, Misericordia
AU - Castañer, Sara
AU - Albertí, Antonia
AU - Bargalló, Nuria
AU - Johnson, Maria
AU - Raymond, Gerald V.
AU - Fatemi, Ali
AU - Moser, Ann B.
AU - Villarroya, Francesc
AU - Portero-Otín, Manuel
AU - Artuch, Rafael
AU - Pamplona, Reinald
AU - Pujol, Aurora
N1 - Funding Information:
Funding Information This study was funded by grants from the Spanish Ministry of Health, Social Services and Equality (EC10-137), the Spanish Institute Health Carlos III (ICI14/0076) (co-funded by European Regional Development Fund, a way to build Europe), the Hesperia Foundation, the European Commission (Leukotreat FP7-241622), and the Autonomous Government of Catalonia (2014SGR1430; 2017SGR1206) to Aurora Pujol. Montserrat Ruiz was funded by the Center for Biomedical Research on Rare Diseases, an initiative of the Institute of Health Carlos III. Stéphane Fourcade was funded by Miguel Servet Program (CPII16/00016) (co-funded by European Social Fund, investing in your future). Alba Naudí, Manuel Portero-Otín, and Reinald Pamplona have received funding support from the Spanish Ministry of Science and Innovation (BFU2009-11879/BFI).
Funding Information:
We thank the Research Centers of Catalonia Programme/Generalitat de Catalunya for institutional support. We thank the patients who freely provided their time and confidence to participate in this study. Logistic support and financial aid for families in need was granted by the Asociaci?n Espa?ola contra las Leucodistrofias. We thank the Clinical Research and Clinical Trials unit of Bellvitge Biomedical Research Institute and the Data Monitoring and Ethics Committee. We also thank Cristina Guilera, Juan Jos? Martinez, and Laia Grau (Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute) for technical assistance.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/10/1
Y1 - 2019/10/1
N2 - 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.
AB - 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.
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U2 - 10.1007/s13311-019-00735-2
DO - 10.1007/s13311-019-00735-2
M3 - Article
C2 - 31077039
AN - SCOPUS:85065730137
VL - 16
SP - 1167
EP - 1182
JO - Neurotherapeutics
JF - Neurotherapeutics
SN - 1933-7213
IS - 4
ER -