Hyperactive PIGGYBAC Transposons for Sustained and Robust Liver-targeted Gene Therapy.

Mario Di Matteo, Ermira Samara, N. Ward, J. Mcvey, Marinee Chuah, Thierry VandenDriessche

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37 Citations (Scopus)


The development of robust non-viral vectors could facilitate clinical gene therapy applications and may overcome some of the immune complications of viral vectors. Nevertheless, most non-viral gene deliver approaches typically yield only transient and/or low gene expression. To address these caveats, we have explored piggyBac transposons to correct hemophilia B by liver-directed factor IX (FIX) gene therapy in hemophilic mice. To achieve this, we combined the use of: (i) a hyperactive codon-optimized piggyBac transposase, (ii) a computationally enhanced liver-specific promoter, (iii) a hyper-functional codon-optimized FIX transgene (FIX R338L Padua) and (iv) a modification of the transposon terminal repeats. This combination strategy resulted in a robust 400-fold improvement in vector performance in hepatocytes yielding stable supra-physiological human FIX activity (>1 year). Liver-specific expression resulted in the induction of FIX-specific immune tolerance. Remarkably, only very low transposon/transposase doses were required to cure the bleeding diathesis. Similarly, PB transposons could be used to express supra-physiologic factor VIII levels using low transposon/transposase doses. PB transposition did not induce tumors in a sensitive hepatocellular carcinoma-prone mouse model. These results underscore the potency and relative safety of the latest generation PB transposons, which constitutes a versatile platform for stable and robust secretion of therapeutic proteins.Molecular Therapy (2014)
Original languageEnglish
Pages (from-to)1614-1624
Number of pages11
JournalMol Ther
Issue numberSeptember
Publication statusPublished - 2014


  • gene therapy
  • Robust Liver-targeted Gene Therapy

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