title: Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy.
abstract: X-linked adrenoleukodystrophy (ALD) is a severe brain demyelinating disease in boys that is caused by a deficiency in ALD protein, an adenosine triphosphate-binding cassette transporter encoded by the ABCD1 gene. ALD progression can be halted by allogeneic hematopoietic cell transplantation (HCT). We initiated a gene therapy trial in two ALD patients for whom there were no matched donors. Autologous CD34+ cells were removed from the patients, genetically corrected ex vivo with a lentiviral vector encoding wild-type ABCD1, and then re-infused into the patients after they had received myeloablative treatment. Over a span of 24 to 30 months of follow-up, we detected polyclonal reconstitution, with 9 to 14% of granulocytes, monocytes, and T and B lymphocytes expressing the ALD protein. These results strongly suggest that hematopoietic stem cells were transduced in the patients. Beginning 14 to 16 months after infusion of the genetically corrected cells, progressive cerebral demyelination in the two patients stopped, a clinical outcome comparable to that achieved by allogeneic HCT. Thus, lentiviral-mediated gene therapy of hematopoietic stem cells can provide clinical benefits in ALD.
authors.affiliation: INSERM UMR745, University Paris-Descartes, 75279 Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Cartier
authors.forename: Salima
authors.initials: S
authors.lastname: Hacein-Bey-Abina
authors.forename: Cynthia C
authors.initials: CC
authors.lastname: Bartholomae
authors.forename: Gabor
authors.initials: G
authors.lastname: Veres
authors.forename: Manfred
authors.initials: M
authors.lastname: Schmidt
authors.forename: Ina
authors.initials: I
authors.lastname: Kutschera
authors.forename: Michel
authors.initials: M
authors.lastname: Vidaud
authors.forename: Ulrich
authors.initials: U
authors.lastname: Abel
authors.forename: Liliane
authors.initials: L
authors.lastname: Dal-Cortivo
authors.forename: Laure
authors.initials: L
authors.lastname: Caccavelli
authors.forename: Nizar
authors.initials: N
authors.lastname: Mahlaoui
authors.forename: Véronique
authors.initials: V
authors.lastname: Kiermer
authors.forename: Denice
authors.initials: D
authors.lastname: Mittelstaedt
authors.forename: Céline
authors.initials: C
authors.lastname: Bellesme
authors.forename: Najiba
authors.initials: N
authors.lastname: Lahlou
authors.forename: François
authors.initials: F
authors.lastname: Lefrère
authors.forename: Stéphane
authors.initials: S
authors.lastname: Blanche
authors.forename: Muriel
authors.initials: M
authors.lastname: Audit
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Payen
authors.forename: Philippe
authors.initials: P
authors.lastname: Leboulch
authors.forename: Bruno
authors.initials: B
authors.lastname: l'Homme
authors.forename: Pierre
authors.initials: P
authors.lastname: Bougnères
authors.forename: Christof
authors.initials: C
authors.lastname: Von Kalle
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Marina
authors.initials: M
authors.lastname: Cavazzana-Calvo
authors.forename: Patrick
authors.initials: P
authors.lastname: Aubourg
mesh_terms: D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000326:Adrenoleukodystrophy / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D000818:Animals; D001921:Brain / Q000473:pathology; D002454:Cell Differentiation; D019070:Cell Lineage; D002648:Child; D018450:Disease Progression; D005227:Fatty Acids / Q000097:blood; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors; D015497:HIV-1 / Q000235:genetics*; D006410:Hematopoiesis; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000502:physiology* / Q000821:virology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000378:metabolism; D019653:Myeloablative Agonists / Q000627:therapeutic use; D014161:Transduction, Genetic; D019172:Transplantation Conditioning; D014182:Transplantation, Autologous; D016662:Virus Integration
chemical_list: C115572:ABCD1 protein, human; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters; D005227:Fatty Acids; D019653:Myeloablative Agonists