title: Lentiviral vector common integration sites in preclinical models and a clinical trial reflect a benign integration bias and not oncogenic selection.
abstract: A recent clinical trial for adrenoleukodystrophy (ALD) showed the efficacy and safety of lentiviral vector (LV) gene transfer in hematopoietic stem progenitor cells. However, several common insertion sites (CIS) were found in patients' cells, suggesting that LV integrations conferred a selective advantage. We performed high-throughput LV integration site analysis on human hematopoietic stem progenitor cells engrafted in immunodeficient mice and found the same CISs reported in patients with ALD. Strikingly, most CISs in our experimental model and in patients with ALD cluster in megabase-wide chromosomal regions of high LV integration density. Conversely, cancer-triggering integrations at CISs found in tumor cells from γ-retroviral vector-based clinical trials and oncogene-tagging screenings in mice always target a single gene and are contained in narrow genomic intervals. These findings imply that LV CISs are produced by an integration bias toward specific genomic regions rather than by oncogenic selection.
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), via Olgettina 58, Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Biffi
authors.forename: Cynthia C
authors.initials: CC
authors.lastname: Bartolomae
authors.forename: Daniela
authors.initials: D
authors.lastname: Cesana
authors.forename: Natalie
authors.initials: N
authors.lastname: Cartier
authors.forename: Patrik
authors.initials: P
authors.lastname: Aubourg
authors.forename: Marco
authors.initials: M
authors.lastname: Ranzani
authors.forename: Martina
authors.initials: M
authors.lastname: Cesani
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Benedicenti
authors.forename: Tiziana
authors.initials: T
authors.lastname: Plati
authors.forename: Enrico
authors.initials: E
authors.lastname: Rubagotti
authors.forename: Stefania
authors.initials: S
authors.lastname: Merella
authors.forename: Alessia
authors.initials: A
authors.lastname: Capotondo
authors.forename: Jacopo
authors.initials: J
authors.lastname: Sgualdino
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Zanetti
authors.forename: Christof
authors.initials: C
authors.lastname: von Kalle
authors.forename: Manfred
authors.initials: M
authors.lastname: Schmidt
authors.forename: Luigi
authors.initials: L
authors.lastname: Naldini
authors.forename: Eugenio
authors.initials: E
authors.lastname: Montini
mesh_terms: D000326:Adrenoleukodystrophy / Q000235:genetics / Q000628:therapy; D000818:Animals; D002986:Clinical Trials as Topic; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D016086:Lentivirus / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D018183:Transplantation Chimera / Q000235:genetics; D016662:Virus Integration / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; C499308:Rag2 protein, mouse