Long-Term Follow-Up of Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy
Abstract
In 2009, cerebral adrenoleukodystrophy (c-ALD) became the first brain disease to be treated with lentiviral (LV)-based hematopoietic stem cell gene therapy with the ABCD1 gene in four boys (P1–P4) who had demyelinating lesions expected to be lethal in the short term and no bone marrow donor. We report the clinical and magnetic resonance imaging (MRI) follow-up over a mean of 8.8 years posttransplant. In parallel, vector genome copies, expression of transgenic ALD protein (ALDP), and viral integration sites were determined in peripheral blood cells. Prior to transplant, the four patients had a normal or near normal neurocognitive status but gadolinium-enhanced demyelination in various brain regions. Gadolinium diffusion disappeared during the first year posttransplant. P3 kept a near normal status until 8.3 years of follow-up, but P1, P2, and P4 showed major cognitive degradation around 9, 28, and 60 months posttransplant. Neurological status and demyelination stabilized until last evaluation in P2, but deteriorated in both P1 at 10 years and P4 at 3 years posttransplant. The proportion of myeloid and lymphoid cells expressing transgenic ALDP decreased by half within 5 years then stabilized around 5% to 10%. Integration site analysis revealed a durable polyclonal distribution of genetically corrected hematopoietic cells. No adverse effects were observed. The long-term arrest of demyelination at MRI and persistence of transduced hematopoietic progenitors support that LV gene therapy may be a safe and durable treatment of c-ALD. However, the neurological degradation observed in three out of four patients mitigates the benefit of this therapy, calling for an earlier intervention, more potent vectors, and additional therapeutic strategies.
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Neuroinflammation recurs 5-10 years after HSC transplantation, as shown by the reappearance of gadolinium extravasation in demyelinated areas and demyelination progression.
“Hence, as would be expected, neuroinflammation recurs 5–10 years after HSC transplantation, as shown by the reappearance of gadolinium extravasation in demyelinated areas and demyelination progression [394].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [394]
The dramatic recurrence of cALD within ten years following transplantation of lentivirus-transduced HSCs demonstrates that primitive mechanisms are not restricted to cells responsible for neuroinflammation.
“This is clearly demonstrated by the dramatic recurrence of cALD within ten years following transplantation of lentivirus-transduced HSCs [394].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [394]
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Self-citationHematopoietic stem-cell gene therapy for cerebral adrenoleukodystrophy
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“…and clinical manifestations, already observed in multiple sclerosis, 34 is likely due to an insufficient sensitivity of routine MRI to detect small demyelination lesions or progression of deleterious glia pathology at the cell level 35 that can nevertheless have a strong clinical impact.”
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Tipanee, J., Samara-Kuko, E., Gevaert, T., Chuah, M. K., & VandenDriessche, T. (2022) · Molecular Therapy · doi:10.1016/j.ymthe.2022.06.006 · Cited by 76 · see citing works
Treatment of cerebral adrenoleukodystrophy: allogeneic transplantation and lentiviral gene therapy
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“There have been two subsequent reports regarding this study, which encompassed a total of 4 patients [72,73].”
ResultGene therapy for the leukodystrophies: From preclinical animal studies to clinical trials.
Metovic, J., Li, Y., Gong, Y., & Eichler, F. (2024) · Neurotherapeutics · doi:10.1016/j.neurot.2024.e00443 · Cited by 16 · see citing works
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Özgür-Günes, Y., Chedik, M., Le Stunff, C., Fovet, C.-M., & Bougnères, P. (2022) · Human Gene Therapy · doi:10.1089/hum.2021.293 · Cited by 10 · see citing works
- Authors
- Bougnères, P., Hacein-Bey-Abina, S., Labik, I., Adamsbaum, C., Castaignède, C., Bellesme, C., & Schmidt, M.
- Affiliations
- UMR1195 INSERM, Le Kremlin Bicêtre, France
- Clinical Immunology Laboratory, Hôpital Kremlin-Bicêtre, Assistance Publique-Hôpitaux de Paris, Université Paris Saclay, Paris, France
- GeneWerk GmbH, Heidelberg, Germany
- Pediatric Radiology and
- Université Paris-Saclay (FR)
- Venue
- Human Gene Therapy
- Publisher
- SAGE Publications
- Published
- 2021-10
- Volume
- 32
- Issue
- 19-20
- Pages
- 1260-1269
- ISSN
- 1043-0342 (ISSN-L)
- 1557-7422
- OpenAlex
- W3141899241
- Cited by
- 45
- References
- 9
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 14 · 2023: 7 · 2022: 11 · 2021: 4
- FWCI
- 5.09
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Gene Therapy (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Agence Nationale de la Recherche (ANR-11-INBS-0011)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- cerebral adrenoleukodystrophy, hematopoietic stem cell gene therapy, long-term follow-up, demyelination, gadolinium-enhanced MRI, cognitive decline, viral integration sites, lentiviral vectors
- MeSH terms
- Adrenoleukodystrophy, Follow-Up Studies, Hematopoietic Stem Cells, Humans, Male, Genetic Therapy, Hematopoietic Stem Cell Transplantation
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