Sleeping Beauty Awakens New Interest

Non-viral gene therapy offers numerous great advantages over viral vectors, with a nearly unlimited packaging capacity and the lack of any viral components or mechanisms that might carry forward the risk of recapitulating viral pathogenesis. The two most significant disadvantages of non-viral systems are (1) that they do not inherently include any mechanism for long-term persistence and (2) that delivery may be inefficient.

The first of these two obstacles has been overcome with the development of the transposons suitable for gene transfer, most notably the Sleeping Beauty (SB) transposase and transposon, which were reconstructed from ancient fish genomes approximately 20 years ago. ¹ While the efficacy of SB has been demonstrated in numerous mammalian species, the efficiency of delivery to large animals after intravenous injection has remained suboptimal.

In this issue, back-to-back papers from the University of Minnesota laboratories of Professors Scott McIvor and Perry Hackett, who incidentally was one of the inventors of the SB system, appear to have overcome this last hurdle. ^2,3 Investigators, working in collaboration with scientists from Discovery Genomics, Inc., optimized a version of hydrodynamic venous delivery to the liver in dogs, using a two-balloon catheter technique to isolate the hepatic venous circulation temporarily from the systemic circulation. Using this innovative endovascular intervention, investigators demonstrated robust expression of secreted reporter genes in dogs, and optimized the hydrodynamic parameters for safety and efficiency. ² Subsequently, this same technique was then used to deliver a number of different secreted transgenes, including using the beta-glucuronidase (GUSB) gene, in a dog model of mucopolysaccharidosis type VII. In the case of the secreted transgenes in dogs with enzyme deficiency, immune suppression and/or macrophage depletion with gadolinium chloride enabled sustained long-term correction.

The significance of these papers is that the great potential of non-viral gene therapy may now be realized by combining this innovative endovascular delivery technique with the SB transposon mechanism of integrating the therapeutic transgene to achieve long-term expression of the therapeutic gene. The possibility that the SB system could be translated to human gene therapy has now become very realistic, potentially in the relatively near future.