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

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 Biotechnol

journal_title

Nature biotechnology

authors

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 L

doi

10.1038/nbt1216

subject

Has Abstract

pub_date

2006-06-01 00:00:00

pages

687-96

issue

6

eissn

1087-0156

issn

1546-1696

pii

nbt1216

journal_volume

24

pub_type

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