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

@article{Montini2006HematopoieticSC,
  title={Hematopoietic stem cell gene transfer in a tumor-prone mouse model uncovers low genotoxicity of lentiviral vector integration},
  author={Eugenio Montini and Daniela Cesana and Manfred Schmidt and Francesca Sanvito and Maurilio Ponzoni and Cynthia C. Bartholomae and Lucia Sergi Sergi and Fabrizio Benedicenti and Alessandro Ambrosi and Clelia Di Serio and Claudio Doglioni and Christof von Kalle and Luigi Naldini},
  journal={Nature Biotechnology},
  year={2006},
  volume={24},
  pages={687-696}
}
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… 
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TLDR
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TLDR
Positive safety data obtained from the testing in highly sensitive preclinical models and in clinical trials of the more advanced lentiviral vectors with self-inactivating (SIN) long terminal repeats (LTRs), have reduced the concerns related to insertional mutagenesis, encouraging the adoption of this vector platform in GT protocols for the treatment of many other diseases.
Lentiviral vector common integration sites in preclinical models and a clinical trial reflect a benign integration bias and not oncogenic selection.
TLDR
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 imply that LV CISs are produced by an integration bias toward specific genomic regions rather than by oncogenic selection.
Aberrant Clonal Hematopoiesis following Lentiviral Vector Transduction of HSPCs in a Rhesus Macaque.
Safety and Ef fi cacy of Retroviral and Lentiviral Vectors for Gene Therapy
TLDR
Positive safety data obtained from the testing in highly sensitive preclinical models and in clinical trials, of the more advanced lentiviral vectors with self-inactivating (SIN) long terminal repeats (LTRs), have reduced the concerns related to insertional mutagenesis, encouraging the adoption of this vector platform in GT protocols for the treatment of many other diseases.
Hepatic lentiviral gene transfer is associated with clonal selection, but not with tumor formation in serially transplanted rodents
TLDR
LV hepatic gene therapy showed a favorable risk profile for stable and long‐term therapeutic gene expression and polyclonality of hepatocyte regeneration was maintained even in an environment of enforced proliferation.
The genotoxic potential of retroviral vectors is strongly modulated by vector design and integration site selection in a mouse model of HSC gene therapy.
TLDR
It is determined that substantially greater LV integration loads are required to approach the same oncogenic risk as gammaRVs, which strongly support the use of SIN viral vector platforms and show that ISS can substantially modulate genotoxicity.
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