title: Efficacy and safety of Sleeping Beauty transposon-mediated gene transfer in preclinical animal studies.
abstract: Sleeping Beauty (SB) transposons have been effective in delivering therapeutic genes to treat certain diseases in mice. Hydrodynamic gene delivery of integrating transposons to 5-20% of the hepatocytes in a mouse results in persistent elevated expression of the therapeutic polypeptides that can be secreted into the blood for activity throughout the animal. An alternative route of delivery is ex vivo transformation with SB transposons of hematopoietic cells, which then can be reintroduced into the animal for treatment of cancer. We discuss issues associated with the scale-up of hydrodynamic delivery to the liver of larger animals as well as ex vivo delivery. Based on our and others' experience with inefficient delivery to larger animals, we hypothesize that impulse, rather than pressure, is a critical determinant of the effectiveness of hydrodynamic delivery. Accordingly, we propose some alterations in delivery strategies that may yield efficacious levels of gene delivery in dogs and swine that will be applicable to humans. To ready hydrodynamic delivery for human application we address a second issue facing transposons used for gene delivery regarding their potential to "re-hop" from one site to another and thereby destabilize the genome. The ability to correct genetic diseases through the infusion of DNA plasmids remains an appealing goal.
authors: Dept. of Genetics, Cell Biology and Development, 321 Church St. SE, Minneapolis, MN 55455, USA. perryh@umn.edu
authors: Perry B
authors: PB
authors: Hackett
authors: Elena L
authors: EL
authors: Aronovich
authors: David
authors: D
authors: Hunter
authors: Myra
authors: M
authors: Urness
authors: Jason B
authors: JB
authors: Bell
authors: Steven J
authors: SJ
authors: Kass
authors: Laurence J N
authors: LJ
authors: Cooper
authors: Scott
authors: S
authors: McIvor
mesh_terms: D000818:Animals; D004251:DNA Transposable Elements / Q000235:genetics*; D004195:Disease Models, Animal; D004285:Dogs; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D005822:Genetic Vectors; D057446:Hydrodynamics; D008107:Liver Diseases / Q000628:therapy; D051379:Mice; D009369:Neoplasms / Q000628:therapy; D012449:Safety; D013552:Swine; D019895:Transposases / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D004251:DNA Transposable Elements; D019895:Transposases; C494471:sleeping beauty transposase, human