Biomarker changes in cerebral adrenoleukodystrophy after gene therapy or allogeneic hematopoietic cell transplant.

Cerebral adrenoleukodystrophy (CALD) is a progressive immune-inflammatory neurologic disease that can be arrested with autologous hematopoietic cell transplant-based gene therapy (GT) or allogeneic hematopoietic cell transplantation (Allo-HCT). We compared transplant types by evaluating changes in two biomarkers, C26:0-lysophosphatidylcholine (C26:0-lysoPC) and neurofilament light chain (NfL), before and 12 months after therapy. Disease severity was quantified by Loes score on MRI. Baseline C26:0-lysoPC was 489 nmol/L for GT recipients and 487 nmol/L for Allo-HCT recipients; it decreased by 6.7% after GT and 48.4% after Allo-HCT (p < 0.0001). Baseline NfL was 17.3 for GT recipients and 35.9 pg/mL for Allo-HCT recipients; it increased by 143% after GT and decreased by 43% after Allo-HCT (p = 0.0006). Loes score progression was greater with GT (+3.0 vs. +1.0 points, p = 0.0134). Multivariate analyses to understand which pre-HCT variable was best associated with disease progression indicated that modality of transplant, GT, was the only significant factor (p = 0.0302).