The aim of this study was to investigate the potential of gene therapy in the treatment of acute intermittent porphyria (AIP), a disorder caused by a partial deficiency of porphobilinogen deaminase (PBGD), the third enzyme in heme synthesis. The condition is biochemically characterized by accumulation of the porphyrin precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG). Here we present the first experiments in vivo using adenoviral vectors to replace the deficient enzyme in the liver of an AIP mouse model. The use of adenoviral vector carrying the cDNA of luciferase in wild-type mice confirmed that transgene expression after intravenous administration was found mainly in liver. When PBGD-deficient mice were administered with adenoviral vector carrying the cDNA of mouse PBGD, the hepatic PBGD activity increased in a dose- and time-dependent manner. The highest activity was found 7 days after injection and remained high after 29 days. The expressed enzyme was shown to correct the metabolic defect in the PBGD-deficient mice as no accumulation of ALA or PBG occurred in plasma, liver, or kidney after induction of heme synthesis by phenobarbital. The study demonstrates that hepatic PBGD expression prevents the accumulation of porphyrin precursors, suggesting a future potential for gene therapy in AIP.
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