Hematopoietic Stem-Cell Gene Therapy Restores White Matter Microvascular Function in Cerebral Adrenoleukodystrophy
Key findings
- In previous work, researchers at Massachusetts General Hospital reported early success in treating cerebral adrenoleukodystrophy (CALD) with autologous hematopoietic stem cells transduced with a Lenti-D lentiviral vector containing ABCD1 carrier DNA
- The objective of this study was to investigate how the gene therapy halts the progression of CALD, using advanced MRI to analyze white matter structural and microvascular changes in 15 boys enrolled in an ongoing study of the therapy
- The dose of ABCD1 gene therapy was inversely correlated with lesion growth, and therapy led to widespread and sustained normalization of white matter permeability and microvascular flow
- An autopsy specimen from a patient who had CALD treated with allogeneic hematopoietic stem-cell transplantation showed the cells can engraft in cerebral vascular and perivascular spaces
- Attenuated progression of CALD associated with the gene therapy may be attributable to normalized interactions between corrected circulating leukocytes and endothelial cells
Cerebral adrenoleukodystrophy (CALD) is the most severe form of adrenoleukodystrophy, a rare X-linked disease caused by a defect in the ABCD1 gene. Nearly always affecting boys under 12 years old, CALD causes inflammation throughout the white matter of the brain, often followed by rapidly progressive neurodegeneration. Most untreated patients are vegetative or dead within a decade of diagnosis.
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The only therapy known to be effective for CALD is allogeneic hematopoietic stem-cell transplantation (allo-HSCT). Unfortunately, its results can be unfavorable if transplantation is not performed early or the burden of cerebral white-matter disease is high at the time of diagnosis.
Researchers at Massachusetts General Hospital recently reported in The New England Journal of Medicine on a gene therapy for CALD in which autologous hematopoietic stem cells are transduced with a Lenti-D lentiviral vector containing ABCD1 carrier DNA. As an alternative to allo-HSCT for children lacking a related donor, the therapy showed great promise. After a median follow-up of 29 months, 88% of patients were alive and had minimal symptoms.
In subsequent research, the team investigated the improvement mechanisms and observed widespread, sustained normalization of white matter permeability and microvascular flow. The findings are detailed in Nature Communications by Arne Lauer, MD, a researcher in the Mass General Department of Neurology, Patricia L. Musolino, MD, PhD, who treats patients in the Neuroscience Intensive Care Unit and the Emergency Department and co-directs the Pediatric Stroke and Cerebrovascular Service, and colleagues.
Methods
The ABCD1 gene therapy continues to be investigated in STARBEAM, a multicenter, open-label phase 2/3 trial. A subcohort of 15 boys, enrolled since October 2013 at Mass General, were recruited for this study. The investigators used advanced MRI techniques to analyze white matter structural and microvascular changes.
Dose-related Response
Gene therapy decelerated the lesion growth rate and halted CALD disease in a large proportion of patients within the observation intervals. The most rapid deceleration occurred after the first post-transplant visit (median days after infusion, 43.5; range, 26-183), followed by less prominent but sustained deceleration over the next two years.
A higher gene dose (higher vector copy number) was associated with less lesion growth.
Effects on Lesions and Microvascular Function
Disruption of the blood–brain barrier, a marker of inflammation in CALD lesions, improved rapidly after gene therapy. This indicates successful early attenuation of microvascular dysfunction.
Furthermore, correction of ABCD1 expression in stem cells normalized capillary flow dynamics beyond the demyelinating lesion.
Stem Cell Engraftment
No brain tissue was available from the patients treated with gene therapy, but the researchers studied a brain autopsy specimen from a boy who died of advanced CALD 15 months after allo-HSCT. This sample demonstrated for the first time that in a patient with adrenoleukodystrophy, hematopoietic stem cells can engraft long-term in the vascular and perivascular spaces of white and gray matter.
Thus, stem cells might provide vascular elements in the cerebral microvasculature that account for changes in the microvascular function of distant normal-appearing white matter.
Toward Clinical Translation
The changes in cerebral white matter microcirculation observed in this study may reflect normalized interactions between corrected circulating leukocytes and endothelial cells that attenuate the progression of CALD. The inverse correlation between gene dose and lesion growth suggests corrected cells contribute to long-term remodeling of brain microvascular function.
Still, it remains unclear whether improved microvascular flow will translate into clinical effects. Indeed, functional outcomes in STARBEAM appear to be worse in patients who receive a lower dose of the gene therapy. It's likely that other contributors to clinical improvement are the halting of CALD demyelination, cessation of cerebral inflammation and an improved metabolic milieu.
Additional research may identify key cells or factors and explain their temporal interaction in the inflammatory process, which may support development of new treatments and improved monitoring of CALD.
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