title: Mouse transplant models for evaluating the oncogenic risk of a self-inactivating XSCID lentiviral vector.
abstract: 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.
authors.affiliation: Division of Experimental Hematology, Department of Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhou
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Ma
authors.forename: Taihe
authors.initials: T
authors.lastname: Lu
authors.forename: Laura
authors.initials: L
authors.lastname: Janke
authors.forename: John T
authors.initials: JT
authors.lastname: Gray
authors.forename: Brian P
authors.initials: BP
authors.lastname: Sorrentino
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002472:Cell Transformation, Viral; D005260:Female; D023061:Gene Order; D005822:Genetic Vectors / Q000009:adverse effects* / Q000235:genetics*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D020648:Peptide Elongation Factor 1 / Q000235:genetics; D013155:Spleen Focus-Forming Viruses / Q000235:genetics; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology / Q000821:virology; D053632:X-Linked Combined Immunodeficiency Diseases / Q000235:genetics
chemical_list: D020648:Peptide Elongation Factor 1