TY - JOUR
T1 - Efficacy and safety of sleeping beauty transposon-mediated gene transfer in preclinical animal studies
AU - Hackett, Perry B.
AU - Aronovich, Elena L.
AU - Hunter, David
AU - Urness, Myra
AU - Bell, Jason B.
AU - Kass, Steven J.
AU - Cooper, Laurence J.N.
AU - McIvor, Scott
PY - 2011/10
Y1 - 2011/10
N2 - 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 ofhydrodynamic 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.
AB - 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 ofhydrodynamic 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.
KW - Chimeric antigen receptors
KW - Clinical applications
KW - Hydrodynamic gene delivery
KW - Non-viral gene delivery
KW - Sleeping beauty transposons
KW - T-cells
UR - http://www.scopus.com/inward/record.url?scp=79955998860&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79955998860&partnerID=8YFLogxK
U2 - 10.2174/156652311797415827
DO - 10.2174/156652311797415827
M3 - Article
C2 - 21888621
AN - SCOPUS:79955998860
SN - 1566-5232
VL - 11
SP - 341
EP - 349
JO - Current gene therapy
JF - Current gene therapy
IS - 5
ER -