Optimized adeno-associated virus 8 produces hepatocyte-specific Cre-mediated recombination without toxicity or affecting liver regeneration

Karen J. Ho, Caroline E. Bass, Alexander H K Kroemer, Chunyan Ma, Ernest Terwilliger, Seth J. Karp

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Engineering viral vectors to produce liver-specific protein expression may help advance understanding of hepatic regeneration and disease states. In addition to introducing genes of interest to the liver, these vectors can be adapted for gene deletion when designed to express Cre recombinase. The ability to use this system requires high, liverrestricted expression, low toxicity, and no effect on the process of interest. We developed an adeno-associated virus 8 (AAV8) with a codon-optimized Cre recombinase under a hepatocyte-specific major urinary protein (MUP) promoter (MUP-iCre-AAV8) that fulfills these requirements. A single intravenous injection of ROSA26R reporter mice, which express lacZ after Cre-mediated recombination, demonstrated homogeneous β-galactosidase expression limited to hepatocytes after only 7 days. Cre protein expression remained strong for at least 31 days. Serum liver function tests and histology demonstrated minimal liver toxicity. The presence of MUP-iCre-AAV8 did not affect hepatocyte proliferation after partial hepatectomy as measured by Ki67 staining. Conclusion: AAV8 with the MUP promoter, by virtue of its lack of hepatic toxicity or effect on liver regeneration, may be an efficient alternative to complex transgenic methodologies for studies of the mouse liver.

Original languageEnglish (US)
Pages (from-to)G412-G419
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume295
Issue number2
DOIs
StatePublished - Aug 2008

Keywords

  • Cre recombinase
  • Hepatotoxicity

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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