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Improved molecular platform for the gene therapy of rare diseases by liver protein secretion

Item Type:Review
Title:Improved molecular platform for the gene therapy of rare diseases by liver protein secretion
Creators Name:Quiviger, M. and Giannakopoulos, A. and Verhenne, S. and Marie, C. and Stavrou, E.F. and Vanhoorelbeke, K. and Izsvák, Z. and De Meyer, S.F. and Athanassiadou, A. and Scherman, D.
Abstract:Many rare monogenic diseases are treated by protein replacement therapy, in which the missing protein is repetitively administered to the patient. However, in several cases, the missing protein is required at a high and sustained level, which renders protein therapy far from being adequate. As an alternative, a gene therapy treatment ensuring a sustained effectiveness would be particularly valuable. Liver is an optimal organ for the secretion and systemic distribution of a therapeutic transgene product. Cutting edge non-viral gene therapy tools were tested in order to produce a high and sustained level of therapeutic protein secretion by the liver using the hydrodynamic delivery technique. The use of S/MAR matrix attachment region provided a slight, however not statistically significant, increase in the expression of a reporter gene in the liver. We have selected the von Willebrand Factor (vWF) gene as a particularly challenging large gene (8.4 kb) for liver delivery and expression, and also because a high vWF blood concentration is required for disease correction. By using the optimized miniplasmid pFAR free of antibiotic resistance gene together with the Sleeping Beauty transposon and the hyperactive SB100X transposase, we have obtained a sustainable level of vWFblood secretion by the liver, at 65% of physiological level. Our results point to the general use of this plasmid platform using the liver as a protein factory to treat numerous rare disorders by gene therapy.
Keywords:Gene Therapy, Miniplasmid, pFAR, Rare Disease, Sleeping Beauty Transposon, S/MAR Attachment Region, Von Willebrand Factor
Source:European Journal of Medical Genetics
Page Range:723-728
Date:November 2018
Official Publication:https://doi.org/10.1016/j.ejmg.2018.04.010
PubMed:View item in PubMed

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