Sleeping Beauty transposon vectors in liver directed gene delivery of LDLR and VLDLR for gene therapy of familial hypercholesterolemia

Tools

Item Type:	Article
Title:	Sleeping Beauty transposon vectors in liver directed gene delivery of LDLR and VLDLR for gene therapy of familial hypercholesterolemia
Creators Name:	Turunen, T.A.K., Kurkipuro, J., Heikura, T., Vuorio, T., Hytönen, E., Izsvák, Z. and Ylä-Herttuala, S.
Abstract:	Plasmid based Sleeping Beauty (SB) transposon vectors were developed and used to deliver genes for low-density-lipoprotein and very-low-density lipoprotein receptors (LDLR and VLDLR, respectively) or lacZ reporter into liver of an LDLR-deficient mouse model of familial hypercholesterolemia (FH). SB transposase, SB100x, was used to integrate the therapeutic transposons into mice livers for evaluating the feasibility of the vectors in reducing high blood cholesterol and the progression of atherosclerosis. Hydrodynamic gene delivery of transposon-VLDLR into the livers of the mice resulted in initial 17-19% reductions in plasma cholesterol, and at the later time-points, in a significant stabilization of the cholesterol level for the 6.5 months duration of the study compared to the control mice. Transposon- LDLR treated animals also demonstrated a trend of stabilization in the cholesterol levels in a long-term. Vector-treated mice had slightly less lipid accumulation in the liver and reduced aortic atherosclerosis. Clinical chemistry and histological analyses revealed normal liver function and morphology comparable to that of the controls during the follow-up with no safety issues regarding the vector type, transgenes, or the gene transfer method. The study demonstrates the safety and potential benefits of the SB transposon vectors in the treatment of FH.
Keywords:	Animal Disease Models, Aorta, Atherosclerosis, Cell Line, DNA Transposable Elements, Gene Expression, Gene Order, Gene Transfer Techniques, Genetic Therapy, Genetic Vectors, Hyperlipoproteinemia Type II, LDL Receptors, Lipids, Liver, Animals, Mice
Source:	Molecular Therapy
ISSN:	1525-0016
Publisher:	Nature Publishing Group
Volume:	24
Number:	3
Page Range:	620-635
Date:	March 2016
Official Publication:	https://doi.org/10.1038/mt.2015.221
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

Repository Staff Only: item control page