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Mol Ther. 2014 Sep;22(9):1605-13. doi: 10.1038/mt.2014.114. Epub 2014 Jun 23.

Liver-specific transcriptional modules identified by genome-wide in silico analysis enable efficient gene therapy in mice and non-human primates.

Author information

  • 11] Department of Gene Therapy & Regenerative Medicine, Free University of Brussels (VUB), Brussels, Belgium [2] Department of Cardiovascular Sciences, Center for Molecular & Vascular Biology, University of Leuven, Leuven, Belgium.
  • 2Department of Cardiovascular Sciences, Center for Molecular & Vascular Biology, University of Leuven, Leuven, Belgium.
  • 3Department for Molecular Biomedical Research (DMBR), VIB - Ghent University, Ghent, Belgium.
  • 41] INSERM UMR 1089, Atlantic Gene Therapies, Université de Nantes, Nantes, France [2] CHU de Nantes, Nantes, France.
  • 5Department of Gene Therapy & Regenerative Medicine, Free University of Brussels (VUB), Brussels, Belgium.
  • 61] Department of Gene Therapy & Regenerative Medicine, Free University of Brussels (VUB), Brussels, Belgium [2] Vesalius Research Center, VIB, Leuven, Belgium [3] University of Leuven, Leuven, Belgium.
  • 71] Vesalius Research Center, VIB, Leuven, Belgium [2] University of Leuven, Leuven, Belgium.
  • 81] Genethon, Evry, France [2] University Pierre and Marie Curie, Paris, France.
  • 91] INSERM, U770, Le Kremlin Bicêtre, France [2] Université Paris-Sud, Le Kremlin Bicêtre, France.

Abstract

The robustness and safety of liver-directed gene therapy can be substantially improved by enhancing expression of the therapeutic transgene in the liver. To achieve this, we developed a new approach of rational in silico vector design. This approach relies on a genome-wide bio-informatics strategy to identify cis-acting regulatory modules (CRMs) containing evolutionary conserved clusters of transcription factor binding site motifs that determine high tissue-specific gene expression. Incorporation of these CRMs into adeno-associated viral (AAV) and non-viral vectors enhanced gene expression in mice liver 10 to 100-fold, depending on the promoter used. Furthermore, these CRMs resulted in robust and sustained liver-specific expression of coagulation factor IX (FIX), validating their immediate therapeutic and translational relevance. Subsequent translational studies indicated that therapeutic FIX expression levels could be attained reaching 20-35% of normal levels after AAV-based liver-directed gene therapy in cynomolgus macaques. This study underscores the potential of rational vector design using computational approaches to improve their robustness and therefore allows for the use of lower and thus safer vector doses for gene therapy, while maximizing therapeutic efficacy.

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