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AIPGENE project: augmenting PBGD expression in the liver as a novel gene therapy for acute intermittent porphyria

Acute intermittent porphyria ( AIP ) is a rare genetic disease in which mutations in the porphobilinogen deaminase ( PBGD ) gene produce insufficient production of a protein necessary for heme synthesis. This leads to an accumulation of toxic intermediates, resulting in a wide variety of problems including acute, severe abdominal pain, psychiatric and neurological disorders, and muscular weakness.
Acute porphyric attacks can be life-threatening and the long-term consequences include irreversible nerve damage, liver cancer and kidney failure.
It is estimated that about 1 in 10,000 Europeans or people of European ancestry carries a mutation in one of the genes for acute porphyria.

The therapies currently available do not prevent the symptoms or consequences of acute porphyric attacks. The only curative therapy is liver transplantation and thus, new curative options are clearly needed.

In 2009, the European Medicines Agency ( EMA ) granted Orphan Drug Designation to AAV5-AAT-PBGD for the treatment of AIP.
AAV is a replication-incompetent virus that has been modified to deliver genes or genetic material into human tissues or cells. AAV5-AAT-PBGD acts by delivering the PBGD expression cassette directly into hepatocytes, in an animal model for acute intermittent porphyria intravenous administration of AAV5-AAT-PBGD.

In heterozygous AIP patient that show 50% of the normal activity the additional PBGD activity will be sufficient to prevent the accumulation of toxic metabolites and thus, to prevent porphyric attacks.

The aim of the project AIPGENE is the clinical development of the orphan drug AAV-AAT-PBGD for use to treat acute intermittent porphyria . The project was performed in two different phases.
In the first phase, a GMP compliant process to produce sufficient AAV5-AAT-PBGD for clinical trials has been developed, and AIP patients have been followed up for a minimum of 6 months before entering the clinical trial.
In the second phase, the safety of AAV5-AAT-PBGD is being explored in a dose escalation. ( Xagena )

Gloria Gonzalez-Aseguinolaza and AIPGENE Consortium, Human Gene Therapy, 2013