Patients with Acute Intermittent Porphyria (AIP) are permanently tired. They continuously suffer acute pain, severe motor affection and an array of neurological problems. AIP affects one in 10,000 people in the EU. But this rare genetic metabolic liver disorder has no curative therapy, except for a liver transplantation. It results from mutations in the so-called, porphobilinogen deaminase (PBGD) gene – which encodes for the production of ‘heme’ enzymes, a chemical compound essential for the function of cells functioning without oxygen, so called aerobic cells. Now, the EU-funded project AIPGENE, due to be completed in 2014 has succeeded in treating eight patients with severe AIP in a phase I clinical trial. The project administered a recombinant adeno-associated vector (AAV), a virus which carries the therapeutic gene. Project coordinator, Gloria González-Aseguinolaza, director of the gene therapy and regulation of gene expression programme at the Centre for Applied Medical Research (CIMA) at the University of Navarra, in Spain, talks to youris.com about the initial results that offer new hope for patients with the disease. What’s wrong with patients with AIP? AIP is a rare disease caused by the accumulation of so-called porphyrin precursors; these are toxic substances that are generated during the heme synthesis pathway, a chemical compound essential for the function of aerobic cells. Current treatment is only palliative and consists of the administration of heme to inhibit the route of heme synthesis and to avoid the accumulation of these precursors. Patients receive this treatment when they suffer an attack caused by uncontrollable exposure to certain agents or to hormonal changes. Some of these attacks are so severe that they can leave the patient completely paralysed for several days or even kill them. What were previous attempts to devise a curative therapy? This is the first gene therapy for a metabolic liver disorder. AIP is a genetic disease caused by the deficiency of a single known gene. AIP patients’ livers are competent in all physiological functions except for the elimination of toxic porphyrin precursors. Thus the transfer of the gene will transform the liver into a completely normal organ. The strategy we are using is the administration of a recombinant adeno-associated vector which carries the therapeutic gene in AIP patients. This recombinant vector has been used previously in clinical trials for the treatment of haemophilia B, Parkinson’s disease, lipoprotein lipase deficiency and a type of inherited blindness. It was administered using different routes depending on the disease. But in common with the haemophilia clinical trial we administer the virus systematically and the target organ is liver. What kind of progress have you made? In this first clinical trial, which will come to an end in September 2014, we have treated eight patients with severe AIP with increasing doses of the virus. None of them has suffered any secondary effect. Therefore we think we have tested the first potentially curative treatment for Porphyria. What are the next steps in your research? We know now that the treatment is safe, which was our first concern. We now have to analyse all the data. This will enable us to see if the treatment has been effective. And then decide whether to carry on in the same way or to change some aspects of the next clinical trial, which will be a phase II trial, beginning in 2015 or 2016. And, ideally, we would like to have a new product on the market around 2020. What impact would successful gene therapy have on patients with AIP and on society? The quality of life of these patients is so poor that a treatment to correct the disease would change theirs and their families’ lives immeasurably. There would also be a major impact on health services. This is because the current heme treatment that they are receiving is expensive and requires hospitalisation.