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Cited by 1,508Virus-based gene therapy researchLysosomal Storage Disorders ResearchMetabolism and Genetic Disorders

Hematopoietic Stem Cell Gene Therapy with a Lentiviral Vector in X-Linked Adrenoleukodystrophy

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Cartier, Nathalie, Hacein-Bey-Abina, Salima, Bartholomae, Cynthia C., Veres, Gabor, Schmidt, Manfred, Kutschera, Ina, Vidaud, Michel, Abel, Ulrich +18 more·2009·Science
DOI 10.1126/science.1171242
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Abstract

Slowing Brain Disease with Gene Therapy: X-linked adrenoleukodystrophy (ALD), the hereditary brain demyelinating disorder that was featured in the movie “ Lorenzo's Oil ,” is typically treated by transplantation of bone marrow from matched donors. This treatment slows progression of the disease by introducing cells that differentiate into myelin-producing cells. Cartier et al. (p. 818 ; see Perspective by Naldini ) tested an alternative gene therapy–based approach in two young patients without matched donors. A lentiviral vector was used to introduce a wild-type copy of the ALD gene into the patients' hematopoietic stem cells ex vivo. The modified cells were then infused back into the patients. Expression of the transferred gene was still detectable in the patients' blood cells 2 years later, and both patients showed neurological improvement and a delay in disease progression comparable to that seen with bone marrow transplants.

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Crossref · 10.1126/science.1171242

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  • Expansions of cells with a common integration site were observed in a gene therapy trial using lentiviral vectors for adrenoleukodystrophy.

    “Expansions of cells with a common integration site were observed in a gene therapy trial using lentiviral vectors for adrenoleukodystrophy [51].”

    From Clinical use of lentiviral vectors (2018) · cites this paper as [51]

    In the section on ex vivo lentiviral-mediated ABCD1 transfer (page not supplied), the authors report that no frequent clone reappeared with an increasing count and that no clonal dominance emerged. They also define common integration sites as insertions in the same gene or region in different clones, not cells sharing one insertion site; their presence did not significantly increase after reinfusion. (LLM, conf=0.88)

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  • Gene therapy has shown potential in various genetic disorders, including X-ALD.

    “Gene therapy is a cutting-edge approach that has shown potential in various genetic disorders, including X-ALD.”

    From X-linked adrenoleukodystrophy and primary adrenal insufficiency (2023) · cites this paper as [48]

    The paper reports clinical benefit from gene therapy in two patients with X-ALD. Its discussion proposes possible applications in other genetic CNS diseases, but does not report that gene therapy has shown potential across various genetic disorders. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Lentiviral vector-based gene transfer into CD34+ HSCs has been applied in the treatment of several genetic diseases, including β-thalassemia, X-linked adrenoleukodystrophy, metachromatic leukodystrophy, and Wiskott-Aldrich Syndrome.

    “Lentiviral vector-based gene transfer into CD34 + HSCs has subsequently been applied in the treatment of several genetic diseases, including β-thalassemia [67], X-linked adrenoleukodystrophy [51], metachromatic leukodystrophy [68, 69], and Wiskott-Aldrich Syndrome [70].”

    From Clinical use of lentiviral vectors (2018) · cites this paper as [51]

  • 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.

    “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 [50]

  • A lentiviral vector has been used to introduce a wild-type copy of the ABCD1 gene into patients' hematopoietic stem cells ex vivo, and the genetically modified cells have been reintroduced into the patients.

    “A lentiviral vector has been used to introduce a wild-type copy of the ABCD1 gene into the patients’ hematopoietic stem cells ex vivo. Subsequently, the genetically modified cells have been reintroduced into the patients (48).”

    From X-linked adrenoleukodystrophy and primary adrenal insufficiency (2023) · cites this paper as [48]

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Cites

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1 of the 40 references couldn’t be matched to a known paper.

Research works printed but not linked: 27

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  27. [30]30. S.H.-B.-A., L.D.-C., L.C., F.L., A.F., and M.C.-C. were supported by INSERM, Assistance Publique-Hôpitaux de Paris, Centre d' Investigation Clinique-Biotherapy, and Association Française contre les Myopathies. C.V.K. and M.S. were supported by grants from the Deutsche Forschungsgemeinschaft (SPP 1230), the German Ministry of Education and Research (TREATID), the Helmholtz Association, and the 6th Framework EEC Programme (CONSERT, CLINIGENE). P. Leboulch owns stock in Genetix Pharmaceuticals, and G. Veres, V. Kiermer, and D. Mittelstaedt were formerly employed at Cell Genesys. This gene therapy trial was approved by AFSSAPS on 15 November 2005 and CCPPRB Paris-Cochin (local Institutional Review Board) on 7 September 2004. Informed consent was obtained from the parents of the patients after the nature and possible consequences of the studies were explained.

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Authors
Cartier, N., Hacein-Bey-Abina, S., Bartholomae, C. C., Veres, G., Schmidt, M., Kutschera, I., Vidaud, M., Abel, U., Dal-Cortivo, L., Caccavelli, L., Mahlaoui, N., Kiermer, V., Mittelstaedt, D., Bellesme, C., Lahlou, N., Lefrère, F., Blanche, S., Audit, M., Payen, E., Leboulch, P., l’Homme, B., Bougnères, P., Von Kalle, C., Fischer, A., Cavazzana-Calvo, M., & Aubourg, P.
Affiliations
  • Inserm (FR)
  • Department of Biotherapy, Hôpital Necker-Enfants Malades, 75743 Paris, France.
  • German Cancer Research Center (DE)
  • 117 Southwest 72nd Place, Gainesville, FL 32608, USA.
  • Hôpital Necker-Enfants Malades (FR)
  • Nature Publishing Group, New York, NY 10013–1917, USA.
  • 13687 Quinton Road, San Diego, CA 92129, USA.
  • Assistance Publique – Hôpitaux de Paris (FR)
  • Hôpital Saint-Vincent-de-Paul (FR)
  • GenoSafe (FR)
  • Brigham and Women's Hospital (US)
  • Department of Pediatric Endocrinology and Neurology, Hôpital Saint-Vincent de Paul, Assistance Publique–Hôpitaux de Paris, 82 Avenue Denfert-Rochereau, 75674 Paris, France.
  • National Center for Tumor Diseases and German Cancer Research Center (Deutsches Krebsforschungszentrum), 69120 Heidelberg, Germany.
Corresponding author
  • Cartier, Nathalie
  • Aubourg, Patrick
ORCID
Venue
Science
Publisher
American Association for the Advancement of Science (AAAS)
Published
2009-11-06
Volume
326
Issue
5954
Pages
818-823
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
DOI
10.1126/science.1171242
OpenAlex
W2141570423
Cited by
1,508
References
40
Citations by year
2026: 25 · 2025: 43 · 2024: 54 · 2023: 50 · 2022: 62 · 2021: 56 · 2020: 71 · 2019: 61 · 2018: 76 · 2017: 96 · 2016: 98 · 2015: 107 · 2014: 130 · 2013: 137 · 2012: 139
FWCI
84.34
Type
journal article
Language
en
Open access
Licence
other-oa
Locations
  • Science (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, other-oa)
Funders
  • Deutsche Forschungsgemeinschaft (SPP 1230)
  • Institut National de la Santé et de la Recherche Médicale
  • Fondation de France
  • Association Européenne contre les Leucodystrophies
  • Assistance publique-Hôpitaux de Paris
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
X-linked adrenoleukodystrophy, hematopoietic stem cell gene therapy, lentiviral vectors, ABCD1 gene, myeloablative conditioning, demyelination
MeSH terms
ATP Binding Cassette Transporter, Subfamily D, Member 1, Adrenoleukodystrophy, Animals, Brain, Cell Differentiation, Child, Fatty Acids, Female, Genetic Vectors, Hematopoiesis, Hematopoietic Stem Cells, Humans, Leukocytes, Mononuclear, Male, Transduction, Genetic, Transplantation, Autologous, Genetic Therapy, HIV-1, Gene Expression, Virus Integration, Microglia, Hematopoietic Stem Cell Transplantation, Disease Progression, ATP-Binding Cassette Transporters, Cell Lineage, Transplantation Conditioning, Myeloablative Agonists, Mice

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