Secondary failure of lentiviral vector gene therapy in a cerebral adrenoleukodystrophy patient with an ABCD1 whole-gene deletion.

A 9-year-old boy with adrenoleukodystrophy due to ABCD1 whole-gene deletion was diagnosed with active cerebral adrenoleukodystrophy characterized by demyelination and gadolinium enhancement on brain MRI. He underwent hematopoietic cell transplant (HCT) with autologous CD34+ cells transduced with an ABCD1-expressing lentiviral vector (eli-cel [elivaldogene autotemcel]) as part of the ALD-104 clinical trial. Fifty days after HCT, the patient's MRI showed gadolinium resolution; the whole-blood vector copy number (VCN) was 0.666 copies/mL. Six months following HCT, an MRI showed re-emergence of gadolinium enhancement; the VCN had decreased to 0.029 copies/mL. Polyclonal antibodies to the ABCD1 gene product were detectable 9 months after transplant, showing reactivity to peroxisomes, suggesting an immune response; however, no antibody binding to human CD34+ cells could be shown. The patient underwent a successful allogeneic HCT 12 months after gene therapy with resultant gadolinium resolution, cerebral disease stabilization, and the disappearance of antibodies. The coincident VCN loss and appearance of antibody to the ABCD1 gene product is of interest, and we postulate that it is related to the patient's whole ABCD1 gene deletion. We suggest close monitoring of loss of gene therapy efficacy due to immune response in patients with full deletions who are considering gene therapy.

Targeting VEGF-mediated blood-brain barrier disruption in advanced cerebral leukodystrophy.

The earliest clinical manifestation of cerebral adrenoleukodystrophy (CALD) is adrenal insufficiency (AI) characterized by elevations in ACTH and loss of cortisol. We showed high (though physiologically achievable) levels of ACTH increases endothelial permeability, increases anisotropy, and increases VEGF secretion. An ACBD1 knockout endothelial cell line had increased sensitivity to ACTH and VEGF. Inhibition of VEGF via application of anti-VEGF (bevacizumab) improved permeability. Six boys with advanced CALD were treated with bevacizumab combined with dexamethasone and ruxolitinib as immune suppressants. Most boys had decreases in gadolinium enhancement on MRI indicating improvement in endothelial function, though all boys continued to progress symptomatically.

Glycoprotein nonmetastatic melanoma protein B (GNMPB) as a novel biomarker for cerebral adrenoleukodystrophy.

Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disease caused by a mutation in the ABCD1 gene, producing mutations in the very long chain fatty acid transporter, ALD protein. Cerebral ALD (cALD) is a severe phenotype of ALD with neuroinflammation and neurodegeneration. Elevated levels of Glycoprotein Nonmetastatic Melanoma Protein B (GNMPB) have been recently documented in neurodegenerative diseases such as Alzheimer's disease, Multiple Sclerosis and Amyotrophic Lateral Sclerosis. Our objective was to measure the levels cerebral spinal fluid (CSF) GNMPB in cALD patients to determine if GNMPB could be a potential biomarker in tracking cALD disease progression. CSF GNMPB levels were significantly higher in cALD patients versus controls (2407 ± 1672 pg/mL vs. 639.5 ± 404 pg/mL, p = 0.0009). We found a positive correlation between CSF GNMPB and MRI disease severity score levels (R2 = 0.3225, p < 0.0001) as well as the gadolinium intensity score (p = 0.0204). Boys with more severe neurologic deficits also had higher levels of CSF GNMPB (p < 0.0001). A positive correlation was shown between CSF GNMPB and another biomarker, chitotriosidase (R2 = 0.2512, p = 0.0244). These data show that GNMPB could be a potential biomarker of cALD disease state and further studies should evaluate it as a predictor of the disease progression.

Evaluation of Neurofilament Light Chain as a Biomarker of Neurodegeneration in X-Linked Childhood Cerebral Adrenoleukodystrophy.

Cerebral adrenoleukodystrophy (CALD) is a devastating, demyelinating neuroinflammatory manifestation found in up to 40% of young males with an inherited mutation in ABCD1, the causative gene in adrenoleukodystrophy. The search for biomarkers which correlate to CALD disease burden and respond to intervention has long been sought after. We used the Olink Proximity Extension Assay (Uppsala, Sweden) to explore the cerebral spinal fluid (CSF) of young males with CALD followed by correlative analysis with plasma. Using the Target 96 Neuro Exploratory panel, we found that, of the five proteins significantly increased in CSF, only neurofilament light chain (NfL) showed a significant correlation between CSF and plasma levels. Young males with CALD had a 11.3-fold increase in plasma NfL compared with controls. Importantly, 9 of 11 young males with CALD who underwent HCT showed a mean decrease in plasma NfL of 50% at 1 year after HCT compared with pre-HCT levels. In conclusion, plasma NfL could be a great value in determining outcomes in CALD and should be scrutinized in future studies in patients prior to CALD development and after therapeutic intervention.