Eggenhofer, Elke and Doenecke, Axel and Renner, Philipp and Slowik, Przemyslaw and Piso, Pompiliu and Geissler, Edward K. and Schlitt, Hans J. and Dahlke, Marc H. and Popp, Felix C. (2010) High volume naked DNA tail-vein injection restores liver function in Fah-knock out mice. JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, 25 (5). pp. 1002-1008. ISSN 0815-9319,
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Background: Despite pharmaceutical treatment with NTBC (2-2-nitro-4-fluoromethylbenzoyl-1,3-cyclohexanedione), a high incidence of liver malignancies occur in humans and mice suffering from hereditary tyrosinemia type 1 (HT1) caused by mutation of the fumarylacetoacetate hydrolase (fah) gene. Methods: To evaluate the efficacy of a definitive treatment for HT1, we transfected fah knockout mice with naked plasmid DNA using high volume tail-vein injection. This approach was chosen to reduce the occurrence of insertional mutagenesis that is frequently observed when using other (retro-)viral vectors. To prolong gene expression, the fah gene was cloned between adeno-associated virus (AAV)-specific inverted terminal repeats (ITRs). Results: All animals treated with high volume plasmid DNA injections could be successfully weaned off NTBC and survived in the long term without any further pharmacological support. Up to 50% fah positive hepatocytes were detected in livers of naked plasmid DNA-treated animals and serum liver function tests approximated those of wild-type controls. Conclusions: Naked plasmid DNA transfection offers a promising alternative treatment for HT1. Minimizing side-effects makes this approach especially appealing.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | TYROSINEMIA TYPE-I; RECOMBINANT ADENOASSOCIATED VIRUS; SITE-SPECIFIC INTEGRATION; GENE-EXPRESSION; PLASMID DNA; FUMARYLACETOACETATE HYDROLASE; HEPATIC-DYSFUNCTION; MURINE MODEL; THERAPY; NTBC; Fah-knockout mouse; gene therapy; hereditary tyrosinemia type 1; insertional mutagenesis; naked DNA plasmid delivery |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Chirurgie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 03 Aug 2020 05:00 |
| Last Modified: | 03 Aug 2020 05:00 |
| URI: | https://pred.uni-regensburg.de/id/eprint/24781 |
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