Porphobilinogen deaminase over-expression in hepatocytes, but not in erythrocytes, prevents accumulation of toxic porphyrin precursors in a mouse model of acute intermittent porphyria
Carmen Unzu (1), Ana Sampedro (1), Itsaso Mauleón (1), Lucía Vanrell (1), Juan Dubrot (1), Rafael Enríquez de Salamanca (2), Gloria González-Aseguinolaza (1), Ignacio Melero [SP] (1), Jesús Prieto (1) and Antonio Fontanellas (1)
(1) Division of Gene Therapy and Hepatology, Centre for Applied Medical Research (CIMA), University of Navarra, Avda. Pio XII, 55, 31008 Pamplona, Spain
(2) Research Center, Hospital Universitario 12 de Octubre, Madrid, Spain
Magazine: Journal of Hepatology
Date: Sep 23, 2009Immunology [SP] Hepatology
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.
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 by hydrodynamic injection plasmids expressing human PBGD or luciferase driven by a liver-specific promoter.
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.
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.
CITATION J Hepatol. 2010 Mar;52(3):417-24
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