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Lymphomagenesis in SCID-X1 mice following lentivirus-mediated phenotype correction independent of insertional mutagenesis and gammac overexpression.
Mol Ther. 2010 May; 18(5):965-76.MT

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 gammac-deficient mice. We observed incomplete or absent T- and B-cell development in mice transplanted with progenitors expressing gammac 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-alpha (EF1alpha) promoter; however, 4 of 14 mice reconstituted with this vector subsequently developed lymphoma. Extensive analyses failed to implicate insertional mutagenesis or gammac 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.

Authors+Show Affiliations

Gene Therapy Research Unit of the Children's Medical Research Institute and The Children's Hospital at Westmead, Westmead, New South Wales, Australia.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20354504

Citation

Ginn, Samantha L., et al. "Lymphomagenesis in SCID-X1 Mice Following Lentivirus-mediated Phenotype Correction Independent of Insertional Mutagenesis and Gammac Overexpression." Molecular Therapy : the Journal of the American Society of Gene Therapy, vol. 18, no. 5, 2010, pp. 965-76.
Ginn SL, Liao SH, Dane AP, et al. Lymphomagenesis in SCID-X1 mice following lentivirus-mediated phenotype correction independent of insertional mutagenesis and gammac overexpression. Mol Ther. 2010;18(5):965-76.
Ginn, S. L., Liao, S. H., Dane, A. P., Hu, M., Hyman, J., Finnie, J. W., Zheng, M., Cavazzana-Calvo, M., Alexander, S. I., Thrasher, A. J., & Alexander, I. E. (2010). Lymphomagenesis in SCID-X1 mice following lentivirus-mediated phenotype correction independent of insertional mutagenesis and gammac overexpression. Molecular Therapy : the Journal of the American Society of Gene Therapy, 18(5), 965-76. https://doi.org/10.1038/mt.2010.50
Ginn SL, et al. Lymphomagenesis in SCID-X1 Mice Following Lentivirus-mediated Phenotype Correction Independent of Insertional Mutagenesis and Gammac Overexpression. Mol Ther. 2010;18(5):965-76. PubMed PMID: 20354504.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Lymphomagenesis in SCID-X1 mice following lentivirus-mediated phenotype correction independent of insertional mutagenesis and gammac overexpression. AU - Ginn,Samantha L, AU - Liao,Sophia H Y, AU - Dane,Allison P, AU - Hu,Min, AU - Hyman,Jessica, AU - Finnie,John W, AU - Zheng,Maolin, AU - Cavazzana-Calvo,Marina, AU - Alexander,Stephen I, AU - Thrasher,Adrian J, AU - Alexander,Ian E, Y1 - 2010/03/30/ PY - 2010/4/1/entrez PY - 2010/4/1/pubmed PY - 2010/7/31/medline SP - 965 EP - 76 JF - Molecular therapy : the journal of the American Society of Gene Therapy JO - Mol. Ther. VL - 18 IS - 5 N2 - 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 gammac-deficient mice. We observed incomplete or absent T- and B-cell development in mice transplanted with progenitors expressing gammac 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-alpha (EF1alpha) promoter; however, 4 of 14 mice reconstituted with this vector subsequently developed lymphoma. Extensive analyses failed to implicate insertional mutagenesis or gammac 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. SN - 1525-0024 UR - https://www.unboundmedicine.com/medline/citation/20354504/Lymphomagenesis_in_SCID_X1_mice_following_lentivirus_mediated_phenotype_correction_independent_of_insertional_mutagenesis_and_gammac_overexpression_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1525-0016(16)31027-9 DB - PRIME DP - Unbound Medicine ER -