Upregulation of PBGD expression in liver as a novel gene therapy for acute intermittent porphyria 2011-2014

Project information

Acute intermittent porphyria (AIP) is a rare genetic disease in which mutations in the porphobilinogen deaminase gene (PBGD) result in insufficient activity of a protein necessary for hemoglobin synthesis. This results in an accumulation of toxic intermediates leading to a wide variety of problems, such as acute and severe abdominal pain, psychiatric and neurological disorders and muscle weakness. Acute porphyric attacks can be life-threatening and lead to long-term consequences such as irreversible nervous system damage, liver cancer and kidney failure.

EPI affects 1/10 000 people in the EU and currently available therapies do not prevent the symptoms or consequences of acute porphyric attacks. The only curative therapy is liver transplantation, so new curative options are clearly needed. In 2009, the European Medicines Agency granted Orphan Drug Designation to AAV5-AAT-PBGD for the treatment of PAI. AAV is a non-replicative virus that has been modified to deliver genes or genetic material to human tissues or cells. AAV5-AAT-PBGD acts by delivering the PBGD expression cassette directly into hepatocytes. In heterozygous PAI patients showing 50% of normal activity, the additional PBGD activity will be sufficient to prevent the accumulation of toxic metabolites and thus to prevent porphyric attacks.

The objective of this project is the clinical development of the orphan drug AAV-AAT-PBGD for use in the treatment of PAI. The project will be developed in three phases. In the first phase, we will develop a GMP-compliant process to produce sufficient AAV5-AAT-PBGD for clinical trials, and create cohorts as large as possible to improve patient follow-up and determine clinical criteria for selecting patients for gene therapy. In the second phase, the safety and efficacy of AAV5-AAT-PBGD will be studied in a dose-intensified Phase I/II clinical trial.

• Duration: 3 years
• Start date: January 1, 2011
• End date: January 1, 2014
• Funder: European Commission – VII Framework Programme
• Grant: 822.840€
• Nature of project: International