CSF and plasma neuro-biomarker dynamics after gene therapy for cerebral adrenoleukodystrophy
T C Lund1, A O Gupta1, S Kemp2
1Department of Pediatrics, Division of Blood and Marrow Transplantation & Cellular Therapy, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Abstract:
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.
Insights
Neurofilament light chain (NfL) shows promise as a biomarker for Cerebral Adrenoleukodystrophy (CALD) treatment. Post-gene therapy, NfL levels predict disease progression, offering insights into treatment effectiveness.
Area of Science:
- Neurology
- Biomarker Discovery
- Gene Therapy
Background:
- Cerebral Adrenoleukodystrophy (CALD) is a severe neurological disorder.
- Current treatments like hematopoietic cell transplant can halt disease progression.
- Biomarkers for monitoring CALD during and after treatment are needed.
Purpose of the Study:
- To identify and evaluate exploratory biomarkers for CALD during gene therapy (GT).
- To assess changes in biomarkers from pre-transplant to two years post-GT.
- To determine the prognostic value of identified biomarkers for CALD progression.
Main Methods:
- Assessed 20 exploratory biomarkers including matrix metalloproteinases, vascular factors, neuroinflammation markers, and lipids.
- Measured biomarker levels pre-transplant and at two years post-GT.
- Correlated biomarker levels with MRI-based Loes scores and analyzed predictive value for disease progression.
Main Results:
- Plasma neuroinflammatory markers, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), showed the most significant changes.
- Pre-GT NfL levels strongly correlated with CALD disease burden (MRI Loes score, R² = 0.8132).
- A median 50% reduction in NfL was observed two years post-GT. NfL levels at 6 months post-GT predicted disease progression at 12 months.
Conclusions:
- NfL is a robust prognostic biomarker for CALD patients undergoing gene therapy.
- NfL levels can predict disease progression following GT for CALD.
- These findings represent the first report of NfL as a prognostic biomarker in response to GT for CALD.
