A transposon and transposase system for human application

Perry B. Hackett, David A. Largaespada, Laurence J.N. Cooper

Research output: Contribution to journalReview articlepeer-review

160 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)674-683
Number of pages10
JournalMolecular Therapy
Volume18
Issue number4
DOIs
StatePublished - Apr 2010

Bibliographical note

Funding Information:
We thank Elena L. Aronovich for helpful discussions. This project was supported by NIH grants P01HD32652 and R01DK082516 to P.B.H., R01CA113636 to D.A.L., and RO1CA124782 and R01CA120956 to L.J.N.C.

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