ADENOVIRAL-MEDIATED EXPRESSION OF PORPHOBILINOGEN DEAMINASE IN LIVER RESTORES THE METABOLIC DEFECT IN A MOUSE MODEL OF ACUTE INTERMITTENT PORPHYRIA

Johansson A1,*, Nowak G2, Möller C3, Blomberg P4, Harper P1

 

1Porphyria Centre Sweden, Division of Clinical Chemistry, 2Division of Transplantation Surgery, Department of Laboratory Medicine, 4Gene Therapy Center, Karolinska University Hospital, Huddinge, 141 86 Stockholm, Sweden, 3HemeBiotech A/S, Lidingö, Sweden, *Annika.Johansson@mssm.edu

 

 

Current treatment of acute intermittent porphyria (AIP) using heme therapy is only palliative and does not prevent acute attacks. New therapeutic alternatives ought to be explored and since AIP is caused by a defect in the porphobilinogen deaminase (PBGD) gene, one obvious strategy would be to use gene therapy.

Here we present the first experiments in vivo using adenoviral vectors to replace the deficient PBGD enzyme in liver of an AIP mouse model. These mice mimic AIP biochemically by increased accumulation of porphyrin precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG) after induction of heme synthesis with phenobarbital. By using an adenoviral vector carrying the luciferase cDNA in wild-type mice it was confirmed that transgene expression after intravenous administration was mainly found in liver.

When PBGD-deficient mice were administered with an adenoviral vector carrying mouse housekeeping PBGD cDNA, the hepatic PBGD activity increased in a dose- and time-dependent manner. Highest activity was found 7 days after injection and remained high after 29 days. The PBGD enzyme did also restore the metabolic defect in the AIP mouse as no accumulation of ALA or PBG was found after induction of heme synthesis in gene therapy treated animals.

This study demonstrates that hepatic PBGD expression prevents accumulation of porphyrin precursors, suggesting a future potential for gene therapy in AIP.