Development of Adenovirus Hybrid Vectors for Sleeping Beauty Transposition in Large Mammals

Martin      Hausl; Wenli      Zhang; Richard      Voigtlander; Nadine      Muther; Christina      Rauschhuber; Anja      Ehrhardt

Abstract

The Sleeping Beauty (SB) transposase system for somatic integration offers great potential for in vivo gene therapeutic applications and genome engineering. Until recently, however, efficacy of SB transposase as a gene transfer vector especially in large animals was lacking. Herein, we report about the newest viral vector development for delivery of the SB transposase system into large mammals. Over the past decade various hyperactive versions of SB transposase and advanced adenovirus vectors enabling efficient and safe delivery of transgenes in vivo were developed. Already several years ago it was demonstrated that adenovirus vectors can be used for delivery of the SB transposase system into murine liver. Our newest study showed for the first time that a hyperactive transposase system delivered by high-capacity adenoviral vectors can result in somatic integration of exogenous DNA in canine liver, facilitating stabilized transgene expression and phenotypic correction for up to three years in a canine model of human disease. In this review we discuss safety issues and further improvements of this adenovirus based hybrid vector system for somatic integration. In the future this approach paves new paths towards the possible cure of human genetic diseases and novel strategies for in vivo genome engineering in large mammals.

Keywords: Adenovirus, Sleeping Beauty transposase, hybrid vector, persistence, somatic integration, large animal, canine, in vivo, phenotype, cellular genes