These authors contributed equally to this work.
Steatohepatitis/Metabolic Liver Disease
Article first published online: 30 NOV 2009
Copyright © 2009 American Association for the Study of Liver Diseases
Volume 51, Issue 4, pages 1200–1208, April 2010
How to Cite
Paulk, N. K., Wursthorn, K., Wang, Z., Finegold, M. J., Kay, M. A. and Grompe, M. (2010), Adeno-associated virus gene repair corrects a mouse model of hereditary tyrosinemia in vivo. Hepatology, 51: 1200–1208. doi: 10.1002/hep.23481
Potential conflict of interest: Nothing to report.
The funding organizations played no role in experimental design, data analysis, or manuscript preparation.
- Issue published online: 26 MAR 2010
- Article first published online: 30 NOV 2009
- Accepted manuscript online: 30 NOV 2009 12:00AM EST
- Manuscript Accepted: 22 NOV 2009
- Manuscript Received: 8 JAN 2009
- National Institute of Diabetes and Digestive and Kidney Diseases. Grant Number: RO1-DK48252
- National Cancer Institute. Grant Number: F31CA130116
Adeno-associated virus (AAV) vectors are ideal for performing gene repair due to their ability to target multiple different genomic loci, low immunogenicity, capability to achieve targeted and stable expression through integration, and low mutagenic and oncogenic potential. However, many handicaps to gene repair therapy remain. Most notable is the low frequency of correction in vivo. To date, this frequency is too low to be of therapeutic value for any disease. To address this, a point-mutation–based mouse model of the metabolic disease hereditary tyrosinemia type I was used to test whether targeted AAV integration by homologous recombination could achieve high-level stable gene repair in vivo. Both neonatal and adult mice were treated with AAV serotypes 2 and 8 carrying a wild-type genomic sequence for repairing the mutated Fah (fumarylacetoacetate hydrolase) gene. Hepatic gene repair was quantified by immunohistochemistry and supported with reverse transcription polymerase chain reaction and serology for functional correction parameters. Successful gene repair was observed with both serotypes but was more efficient with AAV8. Correction frequencies of up to 10−3 were achieved and highly reproducible within typical dose ranges. In this model, repaired hepatocytes have a selective growth advantage and are thus able to proliferate to efficiently repopulate mutant livers and cure the underlying metabolic disease. Conclusion: AAV-mediated gene repair is feasible in vivo and can functionally correct an appropriate selection-based metabolic liver disease in both adults and neonates. (HEPATOLOGY 2010.)