CSF and plasma neuro-biomarker dynamics after gene therapy for cerebral adrenoleukodystrophy

Cerebral adrenoleukodystrophy (CALD) is a progressive, immune-inflammatory neurologic disease that can be arrested through allogeneic or gene-corrected hematopoietic cell transplant. Biomarkers of disease during transplant have not been explored. We assessed 20 exploratory biomarkers, consisting of the matrix metalloproteinase (MMP) family, vascular factors, neuroinflammation, and lipids, to determine changes from baseline pre-transplant to 2 years after gene therapy (GT). We found the most robust changes with the plasma neuroinflammatory markers—neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP). Pre-GT plasma NfL had the strongest correlation with disease burden quantified on MRI by Loes score (R² = 0.8132). On average, patients had a median reduction of 50% in NfL concentration 2 years after GT. NfL levels measured 6 months post-GT were found to predict disease progression, both in terms of absolute Loes score and change in Loes score, at 12 months post-GT in univariate (p = 0.0003) and multivariate analyses (p = 0.0304). These results are the first to report NfL as a prognostic biomarker in response to GT for CALD.