Mouse transplant models for evaluating the oncogenic risk of a self-inactivating XSCID lentiviral vector
- Resource Type
- Authors
- Brian P. Sorrentino; Taihe Lu; Zhijun Ma; John T. Gray; Laura J. Janke; Sheng Zhou
- Source
- PLoS ONE, Vol 8, Iss 4, p e62333 (2013)
PLoS ONE
- Subject
- Mouse
Genetic enhancement
medicine.medical_treatment
T-Lymphocytes
lcsh:Medicine
Hematopoietic stem cell transplantation
X-Linked Combined Immunodeficiency Diseases
Mice
0302 clinical medicine
Peptide Elongation Factor 1
Gene Order
Myeloid Cells
Bone Marrow and Stem Cell Transplantation
Vector (molecular biology)
lcsh:Science
Spleen Focus-Forming Viruses
Non-Hodgkin lymphoma
Mice, Knockout
0303 health sciences
Multidisciplinary
Hematopoietic Stem Cell Transplantation
Hematopoietic stem cell
Gene Therapy
Genomics
Animal Models
Hematology
Acute Lymphoblastic Leukemia
3. Good health
Leukemia
medicine.anatomical_structure
Cell Transformation, Neoplastic
030220 oncology & carcinogenesis
Medicine
Female
Lymphomas
Viral Vectors
Research Article
Acute Myeloid Leukemia
Lymphoma, B-Cell
T cell
Genetic Vectors
Chronic Myeloid Leukemia
Bone Marrow Cells
Biology
Microbiology
Vector Biology
Viral vector
03 medical and health sciences
Model Organisms
Genomic Medicine
Leukemias
medicine
Genetics
Animals
Humans
030304 developmental biology
Clinical Genetics
Severe combined immunodeficiency
Myeloproliferative Disorders
Lentivirus
lcsh:R
Human Genetics
medicine.disease
Cell Transformation, Viral
Hematopoiesis
Immunology
Hematologic cancers and related disorders
lcsh:Q
- Language
- English
- ISSN
- 1932-6203
Hematopoietic stem cell gene therapy requires the use of integrating retroviral vectors in order to stably transmit a therapeutic gene to mature blood cells. Human clinical trials have shown that some vector integration events lead to disrupted regulation of proto-oncogenes resulting in disordered hematopoiesis including T-cell leukemia. Newer vectors have been designed to decrease the incidence of these adverse events but require appropriate pre-clinical assays to demonstrate safety. We have used two distinct mouse serial transplant assays to evaluate the safety of a self-inactivating lentiviral vector intended for use in X-linked severe combined immunodeficiency (XSCID) gene therapy trials. These experiments entailed 28 months of total follow-up and included 386 mice. There were no cases in which the XSCID lentiviral vector clearly caused hematopoietic malignancies, although a single case of B cell malignancy was observed that contained the lentiviral vector as a likely passenger event. In contrast, a SFFV-DsRed γ-retroviral vector resulted in clonal transformation events in multiple secondary recipients. Non-specific pathology not related to vector insertions was noted including T cell leukemias arising from irradiated recipient cells. Overall, this comprehensive study of mouse transplant safety assays demonstrate the relative safety of the XSCID lentiviral vector but also highlight the limitations of these assays.