Hematopoietic stem cell gene transfer in a tumor-prone mouse model uncovers low genotoxicity of lentiviral vector integration

Eugenio Montini, Daniela Cesana, Manfred Schmidt, Francesca Sanvito, Maurilio Ponzoni, Cynthia Bartholomae, Lucia Sergi Sergi, Fabrizio Benedicenti, Alessandro Ambrosi, Clelia Di Serio, Claudio Doglioni, Christof Von Kalle, Luigi Naldini

Research output: Contribution to journalArticlepeer-review

Abstract

Insertional mutagenesis represents a major hurdle to gene therapy and necessitates sensitive preclinical genotoxicity assays. Cdkn2a-/- mice are susceptible to a broad range of cancer-triggering genetic lesions. We exploited hematopoietic stem cells from these tumor-prone mice to assess the oncogenicity of prototypical retroviral and lentiviral vectors. We transduced hematopoietic stem cells in matched clinically relevant conditions, and compared integration site selection and tumor development in transplanted mice. Retroviral vectors triggered dose-dependent acceleration of tumor onset contingent on long terminal repeat activity. Insertions at oncogenes and cell-cycle genes were enriched in early-onset tumors, indicating cooperation in tumorigenesis. In contrast, tumorigenesis was unaffected by lentiviral vectors and did not enrich for specific integrants, despite the higher integration load and robust expression of lentiviral vectors in all hematopoietic lineages. Our results validate a much-needed platform to assess vector safety and provide direct evidence that prototypical lentiviral vectors have low oncogenic potential, highlighting a major rationale for application to gene therapy.

Original languageEnglish
Pages (from-to)687-696
Number of pages10
JournalNature Biotechnology
Volume24
Issue number6
DOIs
Publication statusPublished - Jun 2006

ASJC Scopus subject areas

  • Microbiology

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