Dimethyl Fumarate in Adrenomyeloneuropathy

Adrenoleukodystrophy (X-ALD) is the most prevalent rare genetic disorder affecting the brain's white matter. It is caused by mutations in the ABCD1 gene, which encodes a transporter involved in the degradation of very long-chain fatty acids (VLCFA). As a result, VLCFA accumulate in tissues and plasma, serving as a pathognomonic biomarker for diagnosis. The disease manifests in two main forms: i) adrenomyeloneuropathy (AMN), characterized by chronic progressive spastic paraplegia due to distal axonopathy, and ii) cerebral ALD (cALD), a rapidly progressing and fatal demyelinating leukodystrophy. Current therapeutic options are inadequate, limited to bone marrow transplants and gene therapy for patients with cerebral inflammation. No treatment is available for AMN, which affects 60% of patients.

We have discovered that excess VLCFA leads to mitochondrial reactive oxygen species (ROS) production and oxidative damage, a major factor driving pathogenesis. More recently, we found that the main endogenous response to oxidative damage (the NRF-2 pathway) is impaired in X-ALD. Preclinical tests with an NRF2 activator, specifically the current treatment for multiple sclerosis, dimethyl fumarate (DMF/Tecfidera), showed promising results. All major molecular and cellular pathogenic mechanisms were restored, including: i) mitochondrial function and biogenesis, ii) redox homeostasis, iii) bioenergetic failure, iv) neuroinflammation, along with axonal damage and clinical signs of the disease such as locomotor disability. Consequently, we obtained an international patent for repurposing DMF for X-ALD (US15/957,601) and Orphan Drug Designation by the EMA in 2020 (EMA/OD/0000010028).

Now we are translating this knowledge into a randomized phase IIb/III double-blind placebo-controlled study over 36 months for 40 AMN patients, to determine if DMF is effective in these patients. For the first 24 months, patients will be divided into two groups (placebo and active treatment) in a ratio of 1:2. A 12-month extension phase will follow, during which all patients will receive treatment. Furthermore, we aim to elucidate the molecular mechanisms driving the disease and dissect the redox-inflammatory effects of DMF using an integrative multi-omics approach, which will involve single-cell RNA sequencing in PBMC, and lipidomics in plasma. The clinical and molecular data from historical national and international AMN and cALD cohorts will be pooled to identify markers of severity and progression. Our goal is to address unmet needs in AMN while generating novel fundamental knowledge that will be useful for this and other common axonopathies.