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Hematopoietic Stem Cell Gene Therapy with a Lentiviral Vector in X-Linked Adrenoleukodystrophy
Open accessAbstract
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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“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]
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In the citing paper
“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]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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]
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In the citing paper
“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]
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“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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“The positive results of HSC transplantation into cALD patients [24,356] indicated a role for brain microglia because microglia were thought to originate in bone marrow at that time [357].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [356]
In the citing paper
“In ALD, phagocytes derived from autologous bone marrow transplants likely elicit their beneficial effects by replacing mutant microglia, as they stall terminal neuro-inflammation and demyelination 42.”
From Efficient derivation of microglia-like cells from human pluripotent stem cells (2016) · cites this paper as [42]
In the citing paper
“Allogenic hematopoietic stem cell transplantation [145,146] and autologous stem cell-based gene therapy [147] can arrest the inflammatory demyelinating process with a typical delay of 12–18 months, which has been attributed to the slow replacement of microglia with bone marrow-derived phagocytes [147,148].”
From Peroxisomes in brain development and function (2016) · cites this paper as [147]
In the citing paper
“This is strongly supported by the fact that both allogeneic hematopoietic stem cell (HSC) transplantation and autologous HSC gene therapy are very effective in arresting and even reversing neuroinflammatory cerebral ALD, provided that the procedure is performed at an early stage [101,102].”
From X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects (2012) · cites this paper as [102]
In the citing paper
“In 2009, autologous HSCT was demonstrated to be successful to halt cerebral demyelination in two boys with no compatible donors who received their own genetically corrected stem cells [ 82 ].”
From Peroxisomal ABC Transporters: An Update (2021) · cites this paper as [82]
In the citing paper
“These promising results suggest that such a therapeutic strategy may be as effective as allogeneic HSCT.”
From Peroxisomal ABC Transporters: An Update (2021) · cites this paper as [82]
In the citing paper
“the CD34+ PBMCs (lymphoid and myeloid progenitors) transduced with normal ABCD1 can efficiently correct the clinical phenotype of the X-ALD patients [ 82 ]”
From Peroxisomal ABC Transporters: An Update (2021) · cites this paper as [82]
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Deverman, B. E., Ravina, B. M., Bankiewicz, K. S., Paul, S. M., & Sah, D. W. Y. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2018.158 · Cited by 248
Hematopoietic Stem Cell Gene Therapy: Progress and Lessons Learned
Morgan, R. A., Gray, D., Lomova, A., & Kohn, D. B. (2017) · Cell stem cell · doi:10.1016/j.stem.2017.10.010 · Cited by 252
Biasco, L., Pellin, D., Scala, S., Dionisio, F., Basso-Ricci, L., Leonardelli, L., Scaramuzza, S., Baricordi, C., Ferrua, F., Cicalese, M. P., et al. (2016) · Cell stem cell · doi:10.1016/j.stem.2016.04.016 · Cited by 243
“It will be also important, in future studies, to compare the pattern of reconstitution in our patients with those observed in other GT trials using myeloablative conditioning and in disease contexts where no selective advantage for gene-corrected lymphocytes is expected (Biffi et al., 2013; Cartier et al., 2009).”
ResultSelf-citationMicroglial repopulation model reveals a robust homeostatic process for replacing CNS myeloid cells
Varvel, N. H., Grathwohl, S. A., Baumann, F., Liebig, C., Bosch, A., Brawek, B., Thal, D. R., Charo, I. F., Heppner, F. L., Aguzzi, A., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1210150109 · Cited by 245
“Importantly, microglial apoptosis has been implicated in X-linked adrenoleukodystrophy (ALD) (21), and beneficial clinical outcomes have been reported in ALD patients subject to therapies using nonmutant myeloid cells (47).”
BackgroundBiffi, A., Bartolomae, C. C., Cesana, D., Cartier, N., Aubourg, P. R., Ranzani, M., Cesani, M., Benedicenti, F., Plati, T., Rubagotti, E., et al. (2011) · Blood · doi:10.1182/blood-2010-09-306761 · Cited by 244
Self-citationAdvances in stem cell research and therapeutic development
Luca, M. D., Aiuti, A., Cossu, G., Parmar, M., Pellegrini, G., & Robey, P. G. (2019) · Nature Cell Biology · doi:10.1038/s41556-019-0344-z · Cited by 240
Gene Insertion Into Genomic Safe Harbors for Human Gene Therapy
Papapetrou, E. P., & Schambach, A. (2016) · Molecular Therapy · doi:10.1038/mt.2016.38 · Cited by 238
“Three sites have to date mostly been targeted for transgene addition: (1) the adeno-associated virus site 1 (AAVS1), a naturally occurring site of integration of AAV virus on chromosome 19; (2) the chemokine (C-C motif) receptor 5 (CCR5) gene, a chemokine receptor gene known as an HIV-1 coreceptor; and (3) the human o…”
MethodMicroglia in the CNS: Immigrants from another world
Prinz, M., & Mildner, A. (2010) · Glia · doi:10.1002/glia.21104 · Cited by 245
Lesbats, P., Engelman, A., & Cherepanov, P. (2016) · Chemical Reviews · doi:10.1021/acs.chemrev.6b00125 · Cited by 250
Clinical development of gene therapy: results and lessons from recent successes
Kumar, S. R. P., Markusic, D. M., Biswas, M., High, K. A., & Herzog, R. W. (2016) · Molecular Therapy — Methods & Clinical Development · doi:10.1038/mtm.2016.34 · Cited by 246
The physiological functions of human peroxisomes
Wanders, R. J. A., Baes, M., Ribeiro, D., Ferdinandusse, S., & Waterham, H. R. (2023) · Physiological Reviews · doi:10.1152/physrev.00051.2021 · Cited by 228
Gold nanoparticles (GNPs) in biomedical and clinical applications: A review
Anik, M. I., Mahmud, N., Masud, A. A., & Hasan, M. (2021) · Nano Select · doi:10.1002/nano.202100255 · Cited by 244
Marktel, S., Scaramuzza, S., Cicalese, M. P., Giglio, F., Galimberti, S., Lidonnici, M. R., Calbi, V., Assanelli, A. A., Bernardo, M. E., Rossi, C., et al. (2019) · Nature Medicine · doi:10.1038/s41591-018-0301-6 · Cited by 229
Sather, B. D., Romano Ibarra, G. S., Sommer, K., Curinga, G., Hale, M., Khan, I. F., Singh, S., Song, Y., Gwiazda, K., Sahni, J., et al. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.aac5530 · Cited by 223
“Although this promoter has been shown to be safe and effective in a clinical gene therapy trial (41), future therapeutics may use natural mammalian promoters or include insulators to reduce the potential for insertional mutagenesis or transcriptional silencing (42).”
BackgroundAutologous Ex Vivo Lentiviral Gene Therapy for Adenosine Deaminase Deficiency
Kohn, D. B., Booth, C., Shaw, K. L., Xu‐Bayford, J., Garabedian, E., Trevisan, V., Carbonaro-Sarracino, D. A., Soni, K., Terrazas, D., Snell, K., et al. (2021) · New England Journal of Medicine · doi:10.1056/nejmoa2027675 · Cited by 223
Self-citationFatty acid omega‐oxidation as a rescue pathway for fatty acid oxidation disorders in humans
Wanders, R. J. A., Komen, J. C., & Kemp, S. (2010) · FEBS Journal · doi:10.1111/j.1742-4658.2010.07947.x · Cited by 230
Whole body correction of mucopolysaccharidosis IIIA by intracerebrospinal fluid gene therapy
Haurigot, V., Marcó, S., Ribera, A., Garcia, M., Ruzo, A., Villacampa, P., Ayuso, E., Añor, S., Andaluz, A., Pineda, M., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci66778 · Cited by 215
“Lentiviral vector–mediated transduction of autologous CD34+ HSCs has shown therapeutic efficacy in adrenoleukodystrophy (12), and Authorship note: Virginia Haurigot and Sara Marcó contributed equally to this work.”
van Karnebeek, C., & Stöckler, S. (2011) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2011.11.191 · Cited by 214
Sabatino, D. E., Bushman, F. D., Chandler, R. J., Crystal, R. G., Davidson, B. L., Dolmetsch, R. E., Eggan, K. C., Gao, G., Gil-Fariña, I., Kay, M. A., et al. (2022) · Molecular Therapy · doi:10.1016/j.ymthe.2022.06.004 · Cited by 222
Advances in Gene Delivery Systems
Kamimura, K., Suda, T., Zhang, G., & Liu, D. (2011) · Pharmaceutical Medicine · doi:10.1007/bf03256872 · Cited by 124
“Another successful use of lentiviral vector in a clinical trial was reported for the treatment of X-linked adrenoleukodystrophy due to a deficiency of the ABCD1 gene.([29]) In this trial, progressive cerebral demyelination in two patients was successfully blocked for 14–16 months after lentiviral delivery of wild-type…”
BackgroundResultTurk, B. R., Theda, C., Fatemi, A. S., & Moser, A. B. (2020) · International Journal of Developmental Neuroscience · doi:10.1002/jdn.10003 · Cited by 212
“correction of CD34-positive stem cells is ongoing(Cartier et al., 2009; Eichler et al., 2017).”
BackgroundXu, L., & Anchordoquy, T. (2011) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.22243 · Cited by 209
Gentner, B., Visigalli, I., Hiramatsu, H., Lechman, E. R., Ungari, S., Giustacchini, A., Schira, G., Amendola, M., Quattrini, A., Martino, S., et al. (2010) · Science Translational Medicine · doi:10.1126/scitranslmed.3001522 · Cited by 210
Capotondo, A., Milazzo, R., Politi, L. S., Quattrini, A., Palini, A. G., Plati, T., Merella, S., Nonis, A., Serio, C. D., Montini, E., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1205858109 · Cited by 207
“This scenario is consistent with the results obtained in adrenoleukodystrophy (ALD) patients treated by HSC gene therapy (25).”
ResultA Transposon and Transposase System for Human Application
Hackett, P. B., Largaespada, D. A., & Cooper, L. J. N. (2010) · Molecular Therapy · doi:10.1038/mt.2010.2 · Cited by 209
Friedman, K. M., Garrett, T. E., Evans, J. W., Horton, H. M., Latimer, H. J., Seidel, S. L., Horvath, C. J., & Morgan, R. A. (2018) · Human Gene Therapy · doi:10.1089/hum.2018.001 · Cited by 205
Gene therapy targeting haematopoietic stem cells for inherited diseases: progress and challenges
Cavazzana, M., Bushman, F. D., Miccio, A., André‐Schmutz, I., & Six, E. M. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0020-9 · Cited by 205
Cell-based therapy technology classifications and translational challenges
Mount, N. M., Ward, S., Kefalas, P., & Hyllner, J. (2015) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2015.0017 · Cited by 203
“most common being T cells [5,6,18], HSCs [19–23] and MSCs [23–25].”
BackgroundGenetic treatment of a molecular disorder: gene therapy approaches to sickle cell disease
Hoban, M. D., Orkin, S. H., & Bauer, D. E. (2016) · Blood · doi:10.1182/blood-2015-09-618587 · Cited by 194
“Stable engraftment of 10% to 60% gene-modified HSCs has been observed in other clinical trials with fully cytoablative conditioning.(44,45,128,129) This degree of engraftment would appear to approximate or exceed the threshold required for substantial clinical benefit.”
BackgroundPeroxisomes in brain development and function
Berger, J., Dorninger, F., Forss-Petter, S., & Kunze, M. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2015.12.005 · Cited by 194
Delivery and Specificity of CRISPR/Cas9 Genome Editing Technologies for Human Gene Therapy
Gori, J. L., Hsu, P. D., Maeder, M. L., Shen, S., Welstead, G. G., & Bumcrot, D. A. (2015) · Human Gene Therapy · doi:10.1089/hum.2015.074 · Cited by 200
Viral vectors for therapy of neurologic diseases
Choudhury, S. R., Hudry, E., Maguire, C. A., Sena-Esteves, M., Breakefield, X. O., & Grandi, P. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.02.013 · Cited by 190
“While lentiviral vectors have been used as the vector of choice for ex vivo gene transfer (Cartier et al., 2009), AAV vectors are emerging as the leading delivery vehicle for in vivo gene transfer, including for genetic engineering.”
BackgroundMethodInfluentialUncovering and Dissecting the Genotoxicity of Self-inactivating Lentiviral Vectors In Vivo
Cesana, D., Ranzani, M., Volpin, M., Bartholomae, C., Duros, C., Artus, A., Merella, S., Benedicenti, F., Sergi Sergi, L., Sanvito, F., et al. (2014) · Molecular Therapy · doi:10.1038/mt.2014.3 · Cited by 189
Self-citationViral Vectors in Gene Therapy: Where Do We Stand in 2023?
Lundstrom, K. H. (2023) · Viruses · doi:10.3390/v15030698 · Cited by 208
“In the context of X ‐ linked adrenoleukodystrophy (ALD), SIN ‐ LV vector expressing the adenosine triphosphate ‐ binding cassette transporter (ABCD1) were ex vivo trans ‐ duced into patient ‐ derived autologous CD34 + cells [248].”
Successes and challenges in clinical gene therapy
Kohn, D. B., Chen, Y. Y., & Spencer, M. J. (2023) · Gene Therapy · doi:10.1038/s41434-023-00390-5 · Cited by 209
“Excellent clinical results have also been achieved for several metabolic disorders (lysosomal storage and leukodystrophies) in which monocyte-derived cells — macrophages, microglia — are involved in disease pathogenesis [18 – 20].”
BackgroundX-Linked Adrenoleukodystrophy: Pathogenesis and Treatment
Engelen, M., Kemp, S., & Poll-The, B.-T. (2014) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-014-0486-0 · Cited by 187
Metadata
- 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
- Published
- 2009-11-06
- Volume
- 326
- Issue
- 5954
- Pages
- 818-823
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- 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
- green
- cea.hal.science
- 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 › Genetics (clinical) › 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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