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Evaluating risks of insertional mutagenesis by DNA transposons in gene therapy

  • Perry B. Hackett
    Correspondence
    Reprint requests: Perry B. Hackett, University of Minnesota, Department of Genetics Cell Biology and Development, Center for Genome Engineering and Masonic Cancer Center, Minneapolis, MN 55455
    Affiliations
    Department of Genetics Cell Biology and Development, Center for Genome Engineering and Masonic Cancer Center, University of Minnesota, Minneapolis, Minn
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  • David A. Largaespada
    Affiliations
    Department of Genetics Cell Biology and Development, Center for Genome Engineering and Masonic Cancer Center, University of Minnesota, Minneapolis, Minn
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  • Kirsten C. Switzer
    Affiliations
    Division of Pediatrics and Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, Tex
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  • Laurence J.N. Cooper
    Affiliations
    Division of Pediatrics and Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, Tex
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Published:January 11, 2013DOI:https://doi.org/10.1016/j.trsl.2012.12.005
      Investigational therapy can be successfully undertaken using viral- and nonviral-mediated ex vivo gene transfer. Indeed, recent clinical trials have established the potential for genetically modified T cells to improve and restore health. Recently, the Sleeping Beauty (SB) transposon/transposase system has been applied in clinical trials to stably insert a chimeric antigen receptor (CAR) to redirect T-cell specificity. We discuss the context in which the SB system can be harnessed for gene therapy and describe the human application of SB-modified CAR+ T cells. We have focused on theoretical issues relating to insertional mutagenesis in the context of human genomes that are naturally subjected to remobilization of transposons and the experimental evidence over the last decade of employing SB transposons for defining genes that induce cancer. These findings are put into the context of the use of SB transposons in the treatment of human disease.

      Abbreviations:

      AIDS (acquired immunodeficiency disease syndrome), APC (antigen-presenting cell), CAG (cytomegalovirus beta-actin hybrid promoter), CAR (chimeric antigen receptor), CLL (chronic lymphocytic leukemia), CMV (cytomegalovirus), CRC (clinical research center), DGF (dominant gain of function), DNA (dominant negative gene), ENCODE (encyclopedia of DNA elements), GMP (good manufacturing practices), GOF (gain of function), HIV-1 (human immunodeficiency virus type 1), HLA (human leukocyte antigen), HSC (hematopoietic stem cell), IFN (interferon), IL-2 & IL2 (interleukin type 2), LINE (long interspersed element), LOF (loss of function), LTR (long terminal repeat), MSCV (murine stem cell virus), PCR (polymerase chain reaction), SA (splice acceptor), SB (Sleeping Beauty), SINE (short interspersed element), TA (stacked thymine and adenine basepairs), TAA (tumor-associated antigen), TALEN (transcription factor-like effector nuclease), TG (transgene), ZFN (zinc finger nuclease)
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