The Sleeping Beauty (SB) transposon system is a nonviral vector that directs transgene integration into vertebrate genomes. We hydrodynamically delivered SB transposon plasmids encoding human α-L-iduronidase (hIDUA) at two DNA doses, with and without an SB transposase gene, to NOD.129(B6)-Prkdcscid IDUAtm1Clk/J mice. In transposon-treated, nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice with mucopolysaccharidosis type I (MPS I), plasma IDUA persisted for 18 weeks at levels up to several hundred-fold wild-type (WT) activity, depending on DNA dose and gender. IDUA activity was present in all examined somatic organs, as well as in the brain, and correlated with both glycosaminoglycan (GAG) reduction in these organs and level of expression in the liver, the target of transposon delivery. IDUA activity was higher in the treated males than in females. In females, omission of transposase source resulted in significantly lower IDUA levels and incomplete GAG reduction in some organs, confirming the positive effect of transposition on long-term IDUA expression and correction of the disease. The SB transposon system proved efficacious in correcting several clinical manifestations of MPS I in mice, including thickening of the zygomatic arch, hepatomegaly, and accumulation of foamy macrophages in bone marrow and synovium, implying potential effectiveness of this approach in treatment of human MPS I.
Bibliographical noteFunding Information:
We thank Elizabeth A. Braunlin for testing cardiac function and Vladimir Tsuprun and Sebahattin Cureoglu for testing auditory function of mice; Walter C. Low, and Ilze Matise for helpful discussions; Dan Wolf, Kelly Podetz-Pedersen, and Mayra Garcia-Rivera for assistance with experiments, and the Masonic Cancer Center Comparative Pathology Shared Resource for assistance with pathology assessments (University of Minnesota). This project was supported by grant P01 HD32652 from the National Institutes of Health (NIH) and other funding from Beckman Center for Transposon Research at the University of Minnesota. R.S.M. and P.B.H. have equity in a small biotech company that receives funding from the NIH to explore the use of the SB Transposon System for gene therapy.