title: Porphobilinogen deaminase over-expression in hepatocytes, but not in erythrocytes, prevents accumulation of toxic porphyrin precursors in a mouse model of acute intermittent porphyria.
abstract: OBJECTIVE
  Acute intermittent porphyria (AIP) is characterized by hepatic porphobilinogen deaminase (PBGD) deficiency resulting in a marked overproduction of presumably toxic porphyrin precursors. Our study aimed to assess the protective effects of bone marrow transplantation or PBGD gene transfer into the liver against phenotypic manifestations of acute porphyria attack induced in an AIP murine model.
  
  
  METHODS
  Lethally irradiated AIP mice were intravenously injected with 5x10(6) nucleated bone marrow cells from wild type or AIP donor mice. To achieve liver gene transfer, AIP mice received via hydrodynamic injection plasmids expressing human PBGD or luciferase, driven by a liver-specific promoter.
  
  
  RESULTS
  Erythrocyte PBGD activity increased 2.4-fold in AIP mice receiving bone marrow cells from normal animals. Nevertheless, phenobarbital administration in these mice reproduced key features of acute attacks, such as massively increased urinary porphyrin precursor excretion and decreased motor coordination. Hepatic PBGD activity increased 2.2-fold after hydrodynamic injection of therapeutic plasmid. Mice injected with the luciferase control plasmid showed a high excretion of porphyrin precursors after phenobarbital administration whereas just a small increase was observed in AIP mice injected with the PBGD plasmid. Furthermore, motor disturbance was almost completely abolished in AIP mice treated with the therapeutic plasmid.
  
  
  CONCLUSIONS
  PBGD deficiency in erythroid tissue is not associated with phenotypic manifestations of acute porphyria. In contrast, PBGD over-expression in hepatocytes, albeit in a low proportion, reduced precursor accumulation, which is the hallmark of acute porphyric attacks. Liver-directed gene therapy might offer an alternative to liver transplantation applicable in patients with severe and recurrent manifestations.
authors.affiliation: Division of Gene Therapy and Hepatology, Center for Applied Medical Research, University of Navarra, Avda. Pio XII 55, Pamplona, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Unzu
authors.forename: Ana
authors.initials: A
authors.lastname: Sampedro
authors.forename: Itsaso
authors.initials: I
authors.lastname: Mauleón
authors.forename: Lucía
authors.initials: L
authors.lastname: Vanrell
authors.forename: Juan
authors.initials: J
authors.lastname: Dubrot
authors.forename: Rafael Enríquez
authors.initials: RE
authors.lastname: de Salamanca
authors.forename: Gloria
authors.initials: G
authors.lastname: González-Aseguinolaza
authors.forename: Ignacio
authors.initials: I
authors.lastname: Melero
authors.forename: Jesús
authors.initials: J
authors.lastname: Prieto
authors.forename: Antonio
authors.initials: A
authors.lastname: Fontanellas
mesh_terms: D000622:Aminolevulinic Acid / Q000378:metabolism; D000818:Animals; D016026:Bone Marrow Transplantation; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000378:metabolism* / Q000473:pathology; D005260:Female; D018014:Gene Transfer Techniques; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D011163:Hydroxymethylbilane Synthase / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010957:Plasmids; D011162:Porphobilinogen / Q000378:metabolism; D017118:Porphyria, Acute Intermittent / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D011166:Porphyrins / Q000378:metabolism*
chemical_list: D011166:Porphyrins; D011162:Porphobilinogen; D000622:Aminolevulinic Acid; D011163:Hydroxymethylbilane Synthase