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Mol Ther. 2010 Apr;18(4):674-83. doi: 10.1038/mt.2010.2. Epub 2010 Jan 26.

A transposon and transposase system for human application.

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  • 1Department of Genetics, Cell Biology, and Development, Center for Genome Engineering, Institute of Human Genetics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA.

Abstract

The stable introduction of therapeutic transgenes into human cells can be accomplished using viral and nonviral approaches. Transduction with clinical-grade recombinant viruses offers the potential of efficient gene transfer into primary cells and has a record of therapeutic successes. However, widespread application for gene therapy using viruses can be limited by their initially high cost of manufacture at a limited number of production facilities as well as a propensity for nonrandom patterns of integration. The ex vivo application of transposon-mediated gene transfer now offers an alternative to the use of viral vectors. Clinical-grade DNA plasmids can be prepared at much reduced cost and with lower immunogenicity, and the integration efficiency can be improved by the transient coexpression of a hyperactive transposase. This has facilitated the design of human trials using the Sleeping Beauty (SB) transposon system to introduce a chimeric antigen receptor (CAR) to redirect the specificity of human T cells. This review examines the rationale and safety implications of application of the SB system to genetically modify T cells to be manufactured in compliance with current good manufacturing practice (cGMP) for phase I/II trials.

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