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Expert Opin Biol Ther. 2011 May;11(5):581-93. doi: 10.1517/14712598.2011.562496. Epub 2011 Mar 7.

Genotoxicity of retroviral hematopoietic stem cell gene therapy.

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  • 1Washington State University, Department of Pharmaceutical Sciences and School of Molecular Biosciences, P.O. Box 646534, Pullman, WA 99164-6534, USA.



Retroviral vectors have been developed for hematopoietic stem cell (HSC) gene therapy and have successfully cured X-linked severe combined immunodeficiency (SCID-X1), adenosine deaminase deficiency (ADA-SCID), adrenoleukodystrophy, and Wiskott-Aldrich syndrome. However, in HSC gene therapy clinical trials, genotoxicity mediated by integrated vector proviruses has led to clonal expansion, and in some cases frank leukemia. Numerous studies have been performed to understand the molecular basis of vector-mediated genotoxicity with the aim of developing safer vectors and safer gene therapy protocols. These genotoxicity studies are critical to advancing HSC gene therapy.


This review provides an introduction to the mechanisms of retroviral vector genotoxicity. It also covers advances over the last 20 years in designing safer gene therapy vectors, and in integration site analysis in clinical trials and large animal models. Mechanisms of retroviral-mediated genotoxicity, and the risk factors that contribute to clonal expansion and leukemia in HSC gene therapy are introduced.


Continued research on virus-host interactions and next-generation vectors should further improve the safety of future HSC gene therapy vectors and protocols.

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