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Please use this identifier to cite or link to this item: http://hdl.handle.net/1959.14/356226
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- Title
- Modeling correction of severe urea cycle defects in the growing murine liver using a hybrid recombinant adeno-associated virus/piggyBac transposase gene delivery system
- Related
- Hepatology, Vol. 62, Issue 2, (2015), p.417-428
- DOI
- 10.1002/hep.27842
- Publisher
- Wiley-Blackwell Publishing
- Date
- 2015
- Author/Creator
- Cunningham, Sharon C
- Author/Creator
- Siew, Susan M
- Author/Creator
- Nagy, Andras
- Author/Creator
- Alexander, Ian E
- Author/Creator
- Hallwirth, Claus V
- Author/Creator
- Bolitho, Christine
- Author/Creator
- Sasaki, Natsuki
- Author/Creator
- Garg, Gagan
- Author/Creator
- Michael, Iacovos P
- Author/Creator
- Hetherington, Nicola A
- Author/Creator
- Carpenter, Kevin
- Author/Creator
- de Alencastro, Gustavo
- Description
- Liver-targeted gene therapy based on recombinant adeno-associated viral vectors (rAAV) shows promising therapeutic efficacy in animal models and adult-focused clinical trials. This promise, however, is not directly translatable to the growing liver, where high rates of hepatocellular proliferation are accompanied by loss of episomal rAAV genomes and subsequently a loss in therapeutic efficacy. We have developed a hybrid rAAV/piggyBac transposon vector system combining the highly efficient liver-targeting properties of rAAV with stable piggyBac-mediated transposition of the transgene into the hepatocyte genome. Transposition efficiency was first tested using an enhanced green fluorescent protein expression cassette following delivery to newborn wild-type mice, with a 20-fold increase in stably gene-modified hepatocytes observed 4 weeks posttreatment compared to traditional rAAV gene delivery. We next modeled the therapeutic potential of the system in the context of severe urea cycle defects. A single treatment in the perinatal period was sufficient to confer robust and stable phenotype correction in the ornithine transcarbamylase-deficient Spf(ash) mouse and the neonatal lethal argininosuccinate synthetase knockout mouse. Finally, transposon integration patterns were analyzed, revealing 127,386 unique integration sites which conformed to previously published piggyBac data. CONCLUSION: Using a hybrid rAAV/piggyBac transposon vector system, we achieved stable therapeutic protection in two urea cycle defect mouse models; a clinically conceivable early application of this technology in the management of severe urea cycle defects could be as a bridging therapy while awaiting liver transplantation; further improvement of the system will result from the development of highly human liver-tropic capsids, the use of alternative strategies to achieve transient transposase expression, and engineered refinements in the safety profile of piggyBac transposase-mediated integration.
- Description
- 12 page(s)
- Resource Type
- journal article
- Organisation
- Macquarie University. Department of Chemistry and Biomolecular Sciences
- Identifier
- http://hdl.handle.net/1959.14/356226
- Identifier
- mq:39863
- Identifier
- ISSN:0270-9139
- Identifier
- mq-rm-2013012532
- Identifier
- mq_res-se-310460
- Language
- eng
- Reviewed
Macquarie University ResearchOnline
