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Type: Journal article
Title: Lymphomagenesis in SCID-X1 Mice Following Lentivirus-mediated Phenotype Correction Independent of Insertional Mutagenesis and gamma c Overexpression
Author: Ginn, S.
Liao, S.
Dane, A.
Hu, M.
Hyman, J.
Finnie, J.
Zheng, M.
Cavazzana-Calvo, M.
Alexander, S.
Trasher, A.
Alexander, I.
Citation: Molecular Therapy, 2010; 18(5):965-976
Publisher: Academic Press Inc Elsevier Science
Issue Date: 2010
ISSN: 1525-0016
Statement of
Samantha L Ginn, Sophia HY Liao, Allison P Dane, Min Hu, Jessica Hyman, John W Finnie, Maolin Zheng, Marina Cavazzana-Calvo, Stephen I Alexander, Adrian J Thrasher and Ian E Alexander
Abstract: The development of leukemia as a consequence of vector-mediated genotoxicity in gene therapy trials for X-linked severe combined immunodeficiency (SCID-X1) has prompted substantial research effort into the design and safety testing of integrating vectors. An important element of vector design is the selection and evaluation of promoter-enhancer elements with sufficient strength to drive reliable immune reconstitution, but minimal propensity for enhancer-mediated insertional mutagenesis. In this study, we set out to explore the effect of promoter-enhancer selection on the efficacy and safety of human immunodeficiency virus-1-derived lentiviral vectors in γc-deficient mice. We observed incomplete or absent T- and B-cell development in mice transplanted with progenitors expressing γc from the phosphoglycerate kinase (PGK) and Wiscott–Aldrich syndrome (WAS) promoters, respectively. In contrast, functional T- and B-cell compartments were restored in mice receiving an equivalent vector containing the elongation factor-1-α (EF1α) promoter; however, 4 of 14 mice reconstituted with this vector subsequently developed lymphoma. Extensive analyses failed to implicate insertional mutagenesis or γc overexpression as the underlying mechanism. These findings highlight the need for detailed mechanistic analysis of tumor readouts in preclinical animal models assessing vector safety, and suggest the existence of other ill-defined risk factors for oncogenesis, including replicative stress, in gene therapy protocols targeting the hematopoietic compartment.
Keywords: Cells, Cultured; Animals; Mice, Inbred C57BL; Mice; Mice, SCID; Lentivirus; Lymphoma; Enzyme-Linked Immunosorbent Assay; Oligonucleotide Array Sequence Analysis; Flow Cytometry; Mutagenesis, Insertional; Polymerase Chain Reaction; Genetic Vectors; Interleukin Receptor Common gamma Subunit; X-Linked Combined Immunodeficiency Diseases; Promoter Regions, Genetic; Genetic Therapy
Rights: © 2011 American Society of Gene & Cell Therapy
RMID: 0020096306
DOI: 10.1038/mt.2010.50
Appears in Collections:Pathology publications

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