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…
667 Citations
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References
SHOWING 1-10 OF 59 REFERENCES
High-level β-globin expression and preferred intragenic integration after lentiviral transduction of human cord blood stem cells
- Biology
- 2004
Effective transduction of very primitive human cord blood cells with a candidate therapeutic lentiviral vector resulting in the long-term and robust, erythroidspecific production of therapeutically relevant levels of β-globin protein is indicated.
High-level beta-globin expression and preferred intragenic integration after lentiviral transduction of human cord blood stem cells.
- BiologyThe Journal of clinical investigation
- 2004
Effective transduction of very primitive human cord blood cells with a candidate therapeutic lentiviral vector resulting in the long-term and robust, erythroid-specific production of therapeutically relevant levels of betaA-T87Q-globin protein is indicated.
Distinct Genomic Integration of MLV and SIV Vectors in Primate Hematopoietic Stem and Progenitor Cells
- BiologyPLoS biology
- 2004
Analysis of integration sites in HSCs of rhesus monkeys that had been transplanted 6 mo to 6 y prior with MLV- or SIV-transduced CD34+ cells suggested different mechanisms for integration as well as distinct safety implications for MLV versus SIV vectors.
Inactivation of a GFP retrovirus occurs at multiple levels in long-term repopulating stem cells and their differentiated progeny.
- BiologyBlood
- 2000
Observations suggest at least 2 distinct mechanisms of silencing retrovirally expressed genes in hematopoietic cells, including inactivation downstream of LT-HSC that stably expressed GFP in long-term reconstituted animals.
Retroviral insertional mutagenesis: tagging cancer pathways.
- BiologyAdvances in cancer research
- 2003
Correction of metachromatic leukodystrophy in the mouse model by transplantation of genetically modified hematopoietic stem cells.
- BiologyThe Journal of clinical investigation
- 2004
Ex vivo gene therapy had a significantly higher therapeutic impact than WT HSC transplantation, indicating a critical role for enzyme overexpression in the HSC progeny and indicates that transplantation of LV-transduced autologous HSCs represents a potentially efficacious therapeutic strategy for MLD and possibly other neurodegenerative disorders.
Molecular evidence of lentiviral vector-mediated gene transfer into human self-renewing, multi-potent, long-term NOD/SCID repopulating hematopoietic cells.
- BiologyMolecular therapy : the journal of the American Society of Gene Therapy
- 2002
Although SRC transduction was efficient without stimulation, the presence of cytokines significantly improved it, and the first formal demonstration that primitive human HSC with self-renewal and multi-lineage repopulation capacities were transduced by lentiviral vectors is provided.
Leukemias following retroviral transfer of multidrug resistance 1 (MDR1) are driven by combinatorial insertional mutagenesis.
- Biology, MedicineBlood
- 2005
It is shown that leukemias associated with retroviral expression of MDR1 depend on high vector dose, and involve the selection of clones with combinatorial insertional mutagenesis of proto-oncogenes or other signaling genes, and that insertional mutants can be amplified in vitro before transplantation.
Variegation of retroviral vector gene expression in myeloid cells
- BiologyGene Therapy
- 2000
Both transduced bulk and clonal cell populations displayed a tendency to a progressive extinction of expression over time, with a mechanism involving LTR methylation, which is highly desirable for efficient gene therapy.
Gene transfer by lentiviral vectors is limited by nuclear translocation and rescued by HIV-1 pol sequences
- BiologyNature Genetics
- 2000
The results indicate that nuclear translocation of the genome is a rate-limiting step in lentiviral infection of both dividing and non-dividing cells, and that it depends on protein and nucleic acid sequence determinants.