title: Transduced CD34+ cells from adrenoleukodystrophy patients with HIV-derived vector mediate long-term engraftment of NOD/SCID mice.
abstract: X-linked adrenoleukodystrophy (ALD), an inherited demyelinating disorder of the central nervous system, can be corrected by allogeneic bone marrow transplantation, likely due to the turnover of brain macrophages that are bone marrow derived. ALD is characterized by an accumulation of very long chain fatty acids (VLCFA) due to the deficiency of an ATP binding cassette transporter that imports these fatty acids in peroxisomes. Murine retroviral transduction results in metabolic correction of ALD CD34(+) cells in vitro but reinfusion of these cells into ALD patients would not provide clinical benefit owing to the absence of selective advantage conferred by transgene expression. High-efficiency transduction of ALD CD34(+) peripheral blood mobilized cells was achieved using an HIV-based vector driving ALD gene expression under the elongation factor 1 alpha promoter and a protocol without prestimulation of CD34(+) cells with cytokines prior to transduction to preserve their stem cell properties. Efficient expression of the ALD gene was demonstrated in monocytes/macrophages derived from cultures of transduced ALD CD34(+) cells and in long-term culture initiating cells. VLCFA metabolism was corrected in transduced CD34(+), CFU-derived, and LTC-derived cells, indicating that the vector-encoded ALD protein was fully functional. Transplantation of transduced ALD CD34(+) cells into NOD/SCID mice resulted in long-term expression of ALD protein in monocytes/macrophages derived from engrafted stem cells.
authors.affiliation: INSERM U561, Hôpital Saint Vincent de Paul, 75014 Paris, France.
authors.forename: Sonia
authors.initials: S
authors.lastname: Benhamida
authors.forename: Françoise
authors.initials: F
authors.lastname: Pflumio
authors.forename: Anne
authors.initials: A
authors.lastname: Dubart-Kupperschmitt
authors.forename: Jing Chao
authors.initials: JC
authors.lastname: Zhao-Emonet
authors.forename: Marina
authors.initials: M
authors.lastname: Cavazzana-Calvo
authors.forename: Francis
authors.initials: F
authors.lastname: Rocchiccioli
authors.forename: Serge
authors.initials: S
authors.lastname: Fichelson
authors.forename: Patrick
authors.initials: P
authors.lastname: Aubourg
authors.forename: Pierre
authors.initials: P
authors.lastname: Charneau
authors.forename: Nathalie
authors.initials: N
authors.lastname: Cartier
mesh_terms: D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000326:Adrenoleukodystrophy / Q000097:blood / Q000235:genetics / Q000628:therapy*; D000818:Animals; D018952:Antigens, CD34 / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002470:Cell Survival; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D005434:Flow Cytometry; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006678:HIV / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000276:immunology*; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D020648:Peptide Elongation Factor 1 / Q000235:genetics; D014162:Transfection
chemical_list: C115572:ABCD1 protein, human; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters; D018952:Antigens, CD34; D020648:Peptide Elongation Factor 1