Lentiviral Hematopoietic Cell Gene Therapy for X-Linked Adrenoleukodystrophy
Abstract
X-linked adrenoleukodystrophy (X-ALD) is a severe genetic demyelinating disease caused by a deficiency in ALD protein, an adenosine triphosphate-binding cassette transporter encoded by the ABCD1 gene. When performed at an early stage of the disease, allogeneic hematopoietic stem cell transplantation (HCT) can arrest the progression of cerebral demyelinating lesions. To overcome the limitations of allogeneic HCT, hematopoietic stem cell (HSC) gene therapy strategy aiming to perform autologous transplantation of lentivirally corrected cells was developed. We demonstrated the preclinical feasibility of HSC gene therapy for ALD based on the correction of CD34+ cells from X-ALD patients using an HIV1-derived lentiviral vector. These results prompted us to initiate an HSC gene therapy trial in two X-ALD patients who had developed progressive cerebral demyelination, were candidates for allogeneic HCT, but had no HLA-matched donors or cord blood. Autologous CD34+ cells were purified from the peripheral blood after G-CSF stimulation, genetically corrected ex vivo with a lentiviral vector encoding wild-type ABCD1 cDNA, and then reinfused into the patients after they had received full myeloablative conditioning. Over 3 years of follow-up, the hematopoiesis remained polyclonal in the two patients treated with 7-14% of granulocytes, monocytes, and T and B lymphocytes expressing the lentivirally encoded ALD protein. There was no evidence of clonal dominance or skewing based on the retrieval of lentiviral insertion repertoire in different hematopoietic lineages by deep sequencing. Cerebral demyelination was arrested 14 and 16months, respectively, in the two treated patients, without further progression up to the last follow-up, a clinical outcome that is comparable to that observed after allogeneic HCT. Longer follow-up of these two treated patients and HSC gene therapy performed in additional ALD patients are however needed to evaluate the safety and efficacy of lentiviral HSC gene therapy in cerebral forms of X-ALD.
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Gene transfer using LVVs into CD34+ HSCs has been used to treat several genetic diseases, including b-thalassemia, X-linked adrenoleukodystrophy, metachromatic leukodystrophy, and Wiskott-Aldrich Syndrome.
“Gene transfer using LVVs into CD34 þ HSCs has been used to treat several genetic diseases, including b-thalassemia, 100 X-linked adrenoleukodystrophy, 101 metachromatic leukodystrophy, 102 and Wiskott-Aldrich Syndrome.103”
From Viral Vector Systems for Gene Therapy: A Comprehensive Literature Review of Progress and Biosafety Challenges (2020) · cites this paper as [101]
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- Authors
- Cartier, N., Hacein-Bey-Abina, S., Bartholomae, C. C., Bougnères, P., Schmidt, M., Von Kalle, C., Fischer, A., Cavazzana-Calvo, M., & Aubourg, P.
- Affiliations
- Inserm (FR)
- German Cancer Research Center (DE)
- Venue
- Methods in Enzymology
- Publisher
- Elsevier
- Published
- 2012
- Volume
- 507
- Pages
- 187-198
- ISSN
- 0076-6879 (ISSN-L)
- OpenAlex
- W2183564379
- Cited by
- 123
- References
- 20
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 8 · 2023: 5 · 2022: 8 · 2021: 5 · 2020: 10 · 2019: 8 · 2018: 12 · 2017: 10 · 2016: 8 · 2015: 14 · 2014: 9 · 2013: 16 · 2012: 7
- FWCI
- 36.42
- Type
- book chapter
- Language
- en
- Open access
- closed
- Locations
- Methods in enzymology on CD-ROM/Methods in enzymology (publishedVersion)
- PubMed (publishedVersion)
- 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, autologous stem cell transplantation, CD34+ cells, brain demyelination, clonal dominance, myeloablative conditioning
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily D, Member 1, Adrenoleukodystrophy, Child, Genetic Vectors, Hematopoietic Stem Cells, Humans, Male, Genetic Therapy, Lentivirus, Treatment Outcome, Gene Transfer Techniques, Hematopoietic Stem Cell Transplantation, ATP-Binding Cassette Transporters, HEK293 Cells
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