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.
journal_name
Nat Biotechnoljournal_title
Nature biotechnologyauthors
Montini E,Cesana D,Schmidt M,Sanvito F,Ponzoni M,Bartholomae C,Sergi Sergi L,Benedicenti F,Ambrosi A,Di Serio C,Doglioni C,von Kalle C,Naldini Ldoi
10.1038/nbt1216subject
Has Abstractpub_date
2006-06-01 00:00:00pages
687-96issue
6eissn
1087-0156issn
1546-1696pii
nbt1216journal_volume
24pub_type
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