Effective suicide gene therapy for leukemia in a model of insertional oncogenesis in mice.

Effective suicide gene therapy for leukemia in a model of insertional oncogenesis in mice. Research Abstract Details 

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Effective suicide gene therapy for leukemia in a model of insertional oncogenesis in mice. Abstract Text:

Martina Blumenthal,Dianne Skelton,Karen A Pepper,Thomas Jahn,Emily Methangkool,Donald B Kohn,Martina Blumenthal,Dianne Skelton,Karen A Pepper,Thomas Jahn,Emily Methangkool,Donald B Kohn,

The safety of gene therapy using hematopoietic stem cells may be increased by including a suicide gene in the therapeutic vector to eliminate adverse events like insertional oncogenesis while retaining the clinical benefits. We have developed a model of experimental insertional oncogenesis by transducing the murine factor-dependent leukemia cell line Ba/F3 with a bicistronic Moloney murine leukemia virus retroviral vector encoding a murine oncogene (cKit(D814V)) in addition to one of three suicide genes: Herpes simplex virus thymidine kinase (HSV-TK); SR39, an HSV-TK mutant with an increased affinity for the drug substrate Ganciclovir (GCV); or sc39, a splice-corrected version of SR39. Following intravenous challenge with transduced Ba/F3 clones and treatment with GCV, leukemia developed in mice given cells expressing HSV-TK, but not SR39 or sc39. In vitro GCV resistance was observed in heterogeneously transduced Ba/F3 pools at 2.5-14%, and single-nucleotide changes or partial loss of the suicide gene were identified as mechanisms of drug escape. However, GCV treatment resulted in 80-100% survival of mice challenged even with pools of partially resistant Ba/F3 cells expressing SR39 or sc39. Thus, in this model of vector-driven insertional oncogenesis, a suicide gene approach was effective for eliminating leukemia using modified HSV-TK variants with improved biological activity.Molecular Therapy (2007) 15, 183-192. doi:10.1038/sj.mt.6300015.

Effective suicide gene therapy for leukemia in a model of insertional oncogenesis in mice. Publishing Authors By Initials

M Blumenthal,D Skelton,KA Pepper,T Jahn,E Methangkool,DB Kohn,M Blumenthal,D Skelton,KA Pepper,T Jahn,E Methangkool,DB Kohn,

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Effective suicide gene therapy for leukemia in a model of insertional oncogenesis in mice. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: Molecular therapy : the journal of the American So

VOLUME: 15

Page Numbers: 183-92

Journal Abbreviation: Mol. Ther.

ISSN: 1525-0016

DAY: 13

MONTH: Jan

YEAR: 2007

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LANGUAGE: eng

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AFFILIATION: 1Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, University of Los Angeles, California, USA.

Country: United States

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