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.
Keywords: Sleeping Beauty transposons, hydrodynamic gene delivery, non-viral gene delivery, chimeric antigen receptors, T-cells, clinical applications, episomal DN, SB transposon, chromosome, SB100X
Current Gene Therapy
Title: Efficacy and Safety of Sleeping Beauty Transposon-Mediated Gene Transfer in Preclinical Animal Studies
Volume: 11 Issue: 5
Author(s): Perry B. Hackett, Elena L. Aronovich, David Hunter, Myra Urness, Jason B. Bell, Steven J. Kass, Laurence J.N. Cooper and Scott McIvor
Affiliation:
Keywords: Sleeping Beauty transposons, hydrodynamic gene delivery, non-viral gene delivery, chimeric antigen receptors, T-cells, clinical applications, episomal DN, SB transposon, chromosome, SB100X
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.
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Cite this article as:
B. Hackett Perry, L. Aronovich Elena, Hunter David, Urness Myra, B. Bell Jason, J. Kass Steven, J.N. Cooper Laurence and McIvor Scott, Efficacy and Safety of Sleeping Beauty Transposon-Mediated Gene Transfer in Preclinical Animal Studies, Current Gene Therapy 2011; 11 (5) . https://dx.doi.org/10.2174/156652311797415827
DOI https://dx.doi.org/10.2174/156652311797415827 |
Print ISSN 1566-5232 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5631 |
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