title: High volume naked DNA tail-vein injection restores liver function in Fah-knock out mice.
abstract: 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.
authors.affiliation: Department of Surgery, University Medical Center Regensburg, Regensburg, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Eggenhofer
authors.forename: Axel
authors.initials: A
authors.lastname: Doenecke
authors.forename: Philipp
authors.initials: P
authors.lastname: Renner
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Slowik
authors.forename: Pompiliu
authors.initials: P
authors.lastname: Piso
authors.forename: Edward K
authors.initials: EK
authors.lastname: Geissler
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Schlitt
authors.forename: Marc H
authors.initials: MH
authors.lastname: Dahlke
authors.forename: Felix C
authors.initials: FC
authors.lastname: Popp
mesh_terms: D000818:Animals; D001663:Bilirubin / Q000097:blood; D015415:Biomarkers / Q000097:blood; D049109:Cell Proliferation; D003512:Cyclohexanones / Q000627:therapeutic use; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D015316:Genetic Therapy; D005822:Genetic Vectors; D022781:Hepatocytes / Q000201:enzymology; D006867:Hydrolases / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D007275:Injections, Intravenous; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008099:Liver / Q000201:enzymology*; D008111:Liver Function Tests; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009579:Nitrobenzoates / Q000627:therapeutic use; D010957:Plasmids / Q000008:administration & dosage*; D012709:Serum Albumin / Q000378:metabolism; D013623:Tail / Q000098:blood supply*; D013997:Time Factors; D014162:Transfection; D020176:Tyrosinemias / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000628:therapy*; D014508:Urea / Q000097:blood
chemical_list: D015415:Biomarkers; D003512:Cyclohexanones; D009579:Nitrobenzoates; D012709:Serum Albumin; D014508:Urea; D007770:L-Lactate Dehydrogenase; D006867:Hydrolases; C020156:fumarylacetoacetase; C077073:nitisinone; D001663:Bilirubin