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
Highlights
X-Adrenoleukodystrophy (X-ALD) is the most frequently inherited leukodystrophy, with a minimum incidence of 1 in 14,700 live births [1]
We observed a significant increase in CML, CEL, MDAL, and 8-oxo-dG levels and a trend towards higher AASA levels in the plasma of AMN patients compared with sex- and agematched controls, with CEL levels being the best discriminating factor of genotype (Fig. 2a)
The p value of the likelihood ratio test (LRT, Fig. 6a) indicates that the 6-minute walk test (6MWT) at M0 standing alone is. This open-label trial was primarily envisaged to translate the positive preclinical results obtained on a mouse model of adrenomyeloneuropathy treated with the same combination of antioxidants, by identifying a safe, well-tolerated dose that would achieve biological efficacy in patients
Summary
X-Adrenoleukodystrophy (X-ALD) is the most frequently inherited leukodystrophy, with a minimum incidence of 1 in 14,700 live births [1]. The gene mutated in the disease (ABCD1) encodes the ALD protein (ALDP), a peroxisomal transporter that imports very long-chain fatty acids (VLCFA). Extended author information available on the last page of the article into the peroxisome for degradation [2, 3]. Elevated plasma VLCFA is a pathognomonic biomarker for this disorder, it lacks predictive value for disease severity or progression [4]. All patients who reach adulthood develop the most frequent phenotype, adrenomyeloneuropathy (AMN), in their third and fourth decades of life. The most severe disease phenotype, cerebral childhood adrenoleukodystrophy (cALD), presents rapidly progressive inflammatory brain demyelination with a lethal outcome unless diagnosed early and treated with hematopoietic bone marrow transplant [9] or the new available hematopoietic stem cell therapy [10]
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