Hematopoietic stem-cell gene therapy is associated with restored white matter microvascular function in cerebral adrenoleukodystrophy
Open accessAbstract
Blood-brain barrier disruption marks the onset of cerebral adrenoleukodystrophy (CALD), a devastating cerebral demyelinating disease caused by loss of ABCD1 gene function. The underlying mechanism are not well understood, but evidence suggests that microvascular dysfunction is involved. We analyzed cerebral perfusion imaging in boys with CALD treated with autologous hematopoietic stem-cells transduced with the Lenti-D lentiviral vector that contains ABCD1 cDNA as part of a single group, open-label phase 2-3 safety and efficacy study (NCT01896102) and patients treated with allogeneic hematopoietic stem cell transplantation. We found widespread and sustained normalization of white matter permeability and microvascular flow. We demonstrate that ABCD1 functional bone marrow-derived cells can engraft in the cerebral vascular and perivascular space. Inverse correlation between gene dosage and lesion growth suggests that corrected cells contribute long-term to remodeling of brain microvascular function. Further studies are needed to explore the longevity of these effects.
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In the short term, HSC transplantation reverses neuroinflammation and halts demyelination progression, as indicated by brain MRI.
“In the short term, HSC transplantation reverses neuroinflammation and halts demyelination progression, as indicated by brain MRI [24,392,393].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [393]
In Results and discussion, MRI contrast enhancement, a marker of inflammatory activity, disappeared 60–100 days after allo-HSCT in most patients. The lesion analysis reports that allo-HSCT decelerated lesion growth, while gene therapy halted progression in a large proportion of patients. The claim overstates these findings by saying HSC transplantation reverses neuroinflammation and halts demyelination progression without those qualifications. (LLM, conf=0.88)
Experimental — accuracy not yet measuredEngrafted bone marrow-derived cells were present in the vascular and perivascular white and grey matter spaces.
“Engrafted bone marrow-derived cells were present in the vascular and perivascular white and grey matter spaces.”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [393]
Striking characteristic punctate peroxisomal ALDP expression was found in circulating and perivascular monocytes, endothelium, and pericytes at the demyelinating lesion edge and surrounding cortex.
“while striking characteristic punctate peroxisomal ALDP expression was found in circulating and perivascular monocytes, endothelium, and pericytes at the demyelinating lesion edge and surrounding cortex [393].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [393]
HSC transplantation normalizes white matter permeability and microvascular flow.
“HSC transplantation normalizes white matter permeability and microvascular flow [393].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [393]
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Cites
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Hematopoietic stem-cell gene therapy for cerebral adrenoleukodystrophy
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Self-citationExpression of the adrenoleukodystrophy protein in the human and mouse central nervous system
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Brain endothelial dysfunction in cerebral adrenoleukodystrophy
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Self-citationABCD1 dysfunction alters white matter microvascular perfusion
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Sorted by citations
Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy
Bougnères, P., & Le Stunff, C. (2025) · Genes · doi:10.3390/genes16050590 · Cited by 11 · see citing works
- Authors
- Lauer, A., Speroni, S. L., Choi, M., Da, X., Duncan, C., McCarthy, S., Krishnan, V., Lusk, C. A., Rohde, D., Hansen, M. B., Kalpathy-Cramer, J., Loes, D. J., Caruso, P. A., Williams, D. A., Mouridsen, K., Emblem, K. E., Eichler, F. S., & Musolino, P. L.
- Affiliations
- Heidelberg University (DE)
- Massachusetts General Hospital (US)
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Aarhus University (DK)
- Oslo University Hospital (NO)
- Corresponding author
- Musolino, Patricia L.
- ORCID
- Venue
- Nature Communications
- Published
- 2023-04-05
- Volume
- 14
- Issue
- 1
- Pages
- 1900-1900
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC10076264
- OpenAlex
- W4362606853
- Cited by
- 26
- References
- 7
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 9 · 2023: 3
- FWCI
- 4.32
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (K08 NS094683-01)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- cerebral adrenoleukodystrophy, hematopoietic stem cell gene therapy, ABCD1, blood-brain barrier disruption, brain perfusion imaging, lentiviral vectors, allogeneic hematopoietic stem cell transplantation, gene dosage, demyelination
- MeSH terms
- Adrenoleukodystrophy, Hematopoietic Stem Cells, Humans, Male, Genetic Therapy, Hematopoietic Stem Cell Transplantation, White Matter
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