Pretreatment blood NfL indicates response to cellular therapies in cerebral adrenoleukodystrophy

The neuroinflammatory cerebral form of X-linked adrenoleukodystrophy (CALD) is among the most severe neurological diseases affecting children. Early intervention by hematopoietic stem cell transplantation (HSCT) or gene therapy halts CALD, justifying its inclusion in newborn screening programmes. Currently, eligibility for treatment is assessed using MRI-based Loes and neurological scoring; however, grading poorly differentiates advanced stages or atypical lesion patterns. We recently identified blood neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), indicative of axonal and glial damage, as valid biomarkers reflecting CALD activity. Here, we investigated how pre-treatment biomarker levels relate to outcome of HSCT or gene therapy in a retrospective cohort of 14 paediatric CALD patients aged 5–13 years. Patients were monitored longitudinally before and for up to 5.5 years following HSCT or gene therapy. Disease progression was assessed using MRI-based Loes scoring and neurological evaluations. Plasma NfL and GFAP were quantified using single molecule array (Simoa) technology. Here we show that blood NfL and GFAP transiently increase due to myeloablative conditioning and gradually normalize post-treatment. Pre-treatment NfL ≤ 113 pg/ml, but not GFAP, correlate with CALD stabilization or, for Loes >9, only minor progression. In contrast, NfL >243 pg/ml associates with major progression irrespective of baseline Loes score. In three boys with atypical lesions or advanced disease, NfL outperforms Loes-scoring in predicting outcome. Blood NfL can complement clinical decision-making, particularly in patients with advanced CALD or atypical lesions. These findings are especially relevant for clinical management in countries that have not yet implemented X-linked adrenoleukodystrophy into newborn screening. Cerebral X-linked adrenoleukodystrophy (CALD) is a rare but severe brain disease that mainly affects boys. If treated early with a stem cell transplant or gene therapy, the disease can be stopped. However, deciding who will benefit from treatment is difficult, especially when MRI scans show unusual patterns or the disease is already advanced. In this study, we measured two blood biomarkers, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), indicative of nerve and glial injury. We followed 14 boys with CALD for up to 5.5 years after treatment. We found that the blood NfL level before treatment predicted whether the disease would stabilize or continue to worsen. These findings are especially relevant for doctors in countries that have not yet implemented X-linked adrenoleukodystrophy into newborn screening. Weinhofer et al. examine whether pre-treatment blood neurofilament light chain (NfL) can predict treatment effectiveness in cerebral X-linked adrenoleukodystrophy (CALD). Findings show that blood NfL can complement clinical decision-making, particularly in patients with advanced CALD or atypical lesions.