Liquid biopsy for peripheral disease monitoring in X-ALD

The neurodegenerative disorder X-linked adrenoleukodystrophy (X-ALD) is the most common monogenetically inherited leukodystrophy affecting both children and adults. All X-ALD patients have mutations in the ABCD1 gene encoding a peroxisomal fatty acid transporter. Still, the disorder encompasses remarkably different phenotypes, ranging from a rapidly progressive cerebral inflammation resulting in premature death (cerebral ALD, CALD) to a milder non-inflammatory axonopathy involving the spinal cord and peripheral nerves (Adrenomyeloneuropaty, AMN). No genotype-phenotype correlation exists for the ABCD1 mutations in X-ALD. Accordingly, other genetic, epigenetic or environmental factors, or a combination thereof, are thought to trigger the brain inflammation in CALD. So far, the only treatment option for CALD is bone marrow transplantation or gene therapy involving genetically corrected bone marrow stem cells. However, these treatment regiments are only successful if CALD is recognized in its earliest stages. Although frequent conventional magnetic resonance imaging involving contrast agents is able to detect onset and progression of CALD, this method is associated with limitations as it does not directly report the degree of myelin loss and axonal injury. There is an urgent but currently unmet need for a sensitive, quantitative and easy accessible biomarker that would reveal the onset of CALD in its earliest stages and reflect the axonal damage in AMN patients. The aim of this project is to identify such a blood biomarker by focusing on two pathological key events in X-ALD: neuronal damage and oligodendrocyte cell death. Using blood samples from CALD and AMN patients as well as from healthy controls, we will apply state-of-the art molecular technology techniques like single-molecule array (SiMoA) and Next-Generation Sequencing to evaluate whether axonal damage or oligodendrocyte cell death is reflected by blood neurofilament light chain protein levels or the epigenetic status of cell free DNA. If successful, the results will have direct implications for clinical monitoring of X-ALD patients and for outcome measures in future clinical trials.