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Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy
Open accessAbstract
BACKGROUND: In X-linked adrenoleukodystrophy, mutations in ABCD1 lead to loss of function of the ALD protein. Cerebral adrenoleukodystrophy is characterized by demyelination and neurodegeneration. Disease progression, which leads to loss of neurologic function and death, can be halted only with allogeneic hematopoietic stem-cell transplantation. METHODS: We enrolled boys with cerebral adrenoleukodystrophy in a single-group, open-label, phase 2-3 safety and efficacy study. Patients were required to have early-stage disease and gadolinium enhancement on magnetic resonance imaging (MRI) at screening. The investigational therapy involved infusion of autologous CD34+ cells transduced with the elivaldogene tavalentivec (Lenti-D) lentiviral vector. In this interim analysis, patients were assessed for the occurrence of graft-versus-host disease, death, and major functional disabilities, as well as changes in neurologic function and in the extent of lesions on MRI. The primary end point was being alive and having no major functional disability at 24 months after infusion. RESULTS: A total of 17 boys received Lenti-D gene therapy. At the time of the interim analysis, the median follow-up was 29.4 months (range, 21.6 to 42.0). All the patients had gene-marked cells after engraftment, with no evidence of preferential integration near known oncogenes or clonal outgrowth. Measurable ALD protein was observed in all the patients. No treatment-related death or graft-versus-host disease had been reported; 15 of the 17 patients (88%) were alive and free of major functional disability, with minimal clinical symptoms. One patient, who had had rapid neurologic deterioration, had died from disease progression. Another patient, who had had evidence of disease progression on MRI, had withdrawn from the study to undergo allogeneic stem-cell transplantation and later died from transplantation-related complications. CONCLUSIONS: Early results of this study suggest that Lenti-D gene therapy may be a safe and effective alternative to allogeneic stem-cell transplantation in boys with early-stage cerebral adrenoleukodystrophy. Additional follow-up is needed to fully assess the duration of response and long-term safety. (Funded by Bluebird Bio and others; STARBEAM ClinicalTrials.gov number, NCT01896102 ; ClinicalTrialsRegister.eu number, 2011-001953-10 .).
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“The former is associated with its own degree of morbidity and mortality [62], and both require the patient undergo chemotherapy [48].”
From Structure and Function of the ABCD1 Variant Database: 20 Years, 940 Pathogenic Variants, and 3400 Cases of Adrenoleukodystrophy (2022) · cites this paper as [48]
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“Early-stage treatment of childhood cerebral ALD with hematopoietic stem cell transplantation and, more recently, gene therapy can arrest disease progression if performed in the window of opportunity when the MRI is abnormal but neurological symptoms are not yet apparent [7,38,43,44,45,46,47,48,49,50].”
From Structure and Function of the ABCD1 Variant Database: 20 Years, 940 Pathogenic Variants, and 3400 Cases of Adrenoleukodystrophy (2022) · cites this paper as [48]
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“However, they are useful only as the first signs of abnormalities are noted on magnetic resonance imaging (MRI) of the brain, before the onset of any neurological symptoms.”
From Identification of a Novel Non-Canonical Splice-Site Variant in ABCD1 (2023) · cites this paper as [6]
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“Thus, prompt diagnosis can improve the prognosis of CALD in boys [2,3,4,5,6].”
From Identification of a Novel Non-Canonical Splice-Site Variant in ABCD1 (2023) · cites this paper as [6]
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“Furthermore, an autologous hematopoietic stem cell transplantation after ex vivo lentiviral gene therapy has been developed (Eichler et al., 2017).”
From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Eichler et al., 2017
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“This novel variant was classified as a VUS according to the ACMG PM2, PP3, and PP4 criteria [6], and confirmed using Sanger sequencing (Figure 2B).”
From Identification of a Novel Non-Canonical Splice-Site Variant in ABCD1 (2023) · cites this paper as [6]
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Metadata
- Authors
- Eichler, F., Duncan, C., Musolino, P. L., Orchard, P. J., De Oliveira, S., Thrasher, A. J., Armant, M., Dansereau, C., Lund, T. C., Miller, W. P., Raymond, G. V., Sankar, R., Shah, A. J., Sevin, C., Gaspar, H. B., Gissen, P., Amartino, H., Bratkovic, D., Smith, N. J. C., Paker, A. M., Shamir, E., O’Meara, T., Davidson, D., Aubourg, P., & Williams, D. A.
- Affiliations
- Boston Children's Hospital (US)
- Bluebird Bio (United States) (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2017-10-26
- Volume
- 377
- Issue
- 17
- Pages
- 1630-1638
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC5708849
- OpenAlex
- W2764213443
- Cited by
- 604
- References
- 31
- Citations by year
- 2026: 47 · 2025: 43 · 2024: 96 · 2023: 60 · 2022: 67 · 2021: 79 · 2020: 60 · 2019: 75 · 2018: 63 · 2017: 11
- FWCI
- 37.84
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Wellcome Trust (104807/Z/14/Z)
- National Institutes of Health (UL1TR001102)
- National Institute of Neurological Disorders and Stroke (K08NS094683)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Health Sciences › Medicine › Genetics (clinical) › Lysosomal Storage Disorders Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- cerebral adrenoleukodystrophy, X-linked adrenoleukodystrophy, ABCD1, hematopoietic stem cell gene therapy, lentiviral vectors, demyelination, neurodegeneration, graft-versus-host disease, functional disability, early-stage disease
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily D, Member 1, Adolescent, Adrenoleukodystrophy, Child, Combined Modality Therapy, Genetic Vectors, Hematopoietic Stem Cells, Humans, Male, Transplantation, Autologous, Genetic Therapy, Biomarkers, Lentivirus, Polymerase Chain Reaction, Granulocyte Colony-Stimulating Factor, Hematopoietic Stem Cell Transplantation, ATP-Binding Cassette Transporters, Antigens, CD34
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