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Biomarker Identification, Safety, and Efficacy of High-Dose Antioxidants for Adrenomyeloneuropathy: a Phase II Pilot Study
- Source :
- Dipòsit Digital de la UB, Universidad de Barcelona, Recercat. Dipósit de la Recerca de Catalunya, instname, Neurotherapeutics, Repositorio Abierto de la UdL, Universitad de Lleida
- Publication Year :
- 2019
- Publisher :
- Springer Verlag, 2019.
-
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. ClinicalTrials.gov Identifier: NCT01495260. 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).
- Subjects :
- Male
0301 basic medicine
Oncology
Biomarker identification
Neurology
Neural Conduction
Pilot Projects
medicine.disease_cause
Antioxidants
Pathogenesis
0302 clinical medicine
Hydroxyeicosatetraenoic Acids
oxidative stress
Medicine
Pharmacology (medical)
Prospective Studies
Adrenoleukodystrophy
Chemokine CCL2
Biochemical markers
Middle Aged
Inflamació
3. Good health
Treatment Outcome
Marcadors bioquímics
Original Article
Female
Inflammation Mediators
medicine.symptom
inflammation
Adult
medicine.medical_specialty
Inflammation
Culprit
Young Adult
03 medical and health sciences
Internal medicine
Humans
Adrenomyeloneuropathy
Pharmacology
Dose-Response Relationship, Drug
business.industry
biomarkers
Clinical trial
030104 developmental biology
Oxidative stress
Neurology (clinical)
business
030217 neurology & neurosurgery
Homeostasis
Biomarkers
Follow-Up Studies
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Dipòsit Digital de la UB, Universidad de Barcelona, Recercat. Dipósit de la Recerca de Catalunya, instname, Neurotherapeutics, Repositorio Abierto de la UdL, Universitad de Lleida
- Accession number :
- edsair.doi.dedup.....0da5c85461de28c728b1cfe5df5a97ed