title: Parallel assessment of globin lentiviral transfer in induced pluripotent stem cells and adult hematopoietic stem cells derived from the same transplanted β-thalassemia patient.
abstract: A patient with β(E)/β(0) -thalassemia major was converted to transfusion-independence 4.5 years ago by lentiviral gene transfer in hematopoietic stem cells while showing a myeloid-biased cell clone. Induced pluripotent stem cells (iPSCs) are a potential alternative source of hematopoietic stem cells. If fetal to adult globin class, switching does not occur in vivo in iPSC-derived erythroid cells, β-globin gene transfer would be unnecessary. To investigate both vector integration skewing and the potential use of iPSCs for the treatment of thalassemia, we derived iPSCs from the thalassemia gene therapy patient and compared iPSC-derived hematopoietic cells to their natural isogenic somatic counterparts. In NSG immunodeficient mice, embryonic to fetal and a partial fetal to adult globin class switching were observed, indicating that the gene transfer is likely necessary for iPSC-based therapy of the β-hemoglobinopathies. Lentivector integration occurred in regions of low and high genotoxicity. Surprisingly, common integration sites (CIS) were identified across those iPSCs and cells retrieved from isogenic and nonisogenic gene therapy patients with β-thalassemia and adrenoleukodystrophy, respectively. This suggests that CIS observed in the absence of overt tumorigenesis result from nonrandom lentiviral integration rather than oncogenic in vivo selection. These findings bring the use of iPSCs closer to practicality and further clarify our interpretation of genome-wide lentivector integration.
authors.affiliation: CEA, Institute of Emerging Diseases and Innovative Therapies (iMETI), Fontenay aux Roses, France; INSERM U962 and University Paris Sud 11; Thalassemia Research Centre, Institute of Molecular Biosciences, Mahidol University, Nakornpathom, Thailand; Department of Biochemistry, Faculty of Medicine, Siriraj Hospital, Mahidol University, Nakornpathom, Thailand.
authors.forename: Alisa
authors.initials: A
authors.lastname: Tubsuwan
authors.forename: Soumeya
authors.initials: S
authors.lastname: Abed
authors.forename: Annette
authors.initials: A
authors.lastname: Deichmann
authors.forename: Melanie D
authors.initials: MD
authors.lastname: Kardel
authors.forename: Cynthia
authors.initials: C
authors.lastname: Bartholomä
authors.forename: Alice
authors.initials: A
authors.lastname: Cheung
authors.forename: Olivier
authors.initials: O
authors.lastname: Negre
authors.forename: Zahra
authors.initials: Z
authors.lastname: Kadri
authors.forename: Suthat
authors.initials: S
authors.lastname: Fucharoen
authors.forename: Christof
authors.initials: C
authors.lastname: von Kalle
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Payen
authors.forename: Stany
authors.initials: S
authors.lastname: Chrétien
authors.forename: Manfred
authors.initials: M
authors.lastname: Schmidt
authors.forename: Connie J
authors.initials: CJ
authors.lastname: Eaves
authors.forename: Philippe
authors.initials: P
authors.lastname: Leboulch
authors.forename: Leïla
authors.initials: L
authors.lastname: Maouche-Chrétien
mesh_terms: D000328:Adult; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D041905:Erythroid Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005822:Genetic Vectors / Q000378:metabolism; D005914:Globins / Q000235:genetics* / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016086:Lentivirus / Q000378:metabolism*; D051379:Mice; D009153:Mutagens / Q000633:toxicity; D012038:Regeneration / Q000187:drug effects; D014161:Transduction, Genetic; D016662:Virus Integration / Q000187:drug effects; D017086:beta-Thalassemia / Q000473:pathology*
chemical_list: D009153:Mutagens; D005914:Globins
keywords: Human induced pluripotent stem cells Gene therapy Hematopoietic stem cells Thalassemia β-Globin expression