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Changing your DNA to treat disease

AIP researchers have used a virus to deliver a healthy gene to people with a faulty version. Image: Courtesy of AIPGENE
AIP researchers have used a virus to deliver a healthy gene to people with a faulty version. Image: Courtesy of AIPGENE

Scientists have worked out how to fix broken genes by inserting new ones into people's DNA, and they've now successfully tested the technique on sufferers of a rare liver disease.

Between 30 and 40 million people in Europe suffer from rare diseases and many of these diseases have genetic origins.

While some rare genetic diseases are complex, many are caused by faults in a single gene. Many of these patients could in theory be treated by using a virus to insert a new gene into their genome, thereby correcting the errors that caused the disease.

Researchers on the EU-funded AIPGENE project have used the technique, known as gene therapy, to insert a new copy of a gene into people who suffer from the rare genetic liver disease acute intermittent porphyria (AIP). The disease affects one in 10 000 people in the EU, with symptoms during a severe attack ranging from intense abdominal pain and neurological problems to temporary paralysis and death.

The researchers successfully concluded early stage tests on humans, taking them one step closer to developing gene therapy for liver disease and making AIP one of the first diseases that could be treated using this technique. In the Western world only one gene therapy drug has so far been approved for use, although it is not yet commercially available. 

AIP is caused by a mutation in a gene which is involved in making a chemical compound called heme. Heme is essential for the function of aerobic cells but, in people with AIP, the production process gets stuck and ingredient molecules build up to toxic levels.

Currently the only cure for AIP is a liver transplant. However, if the single faulty gene could be replaced with a functioning version, it would provide an alternative cure for people with the disease.

Synthetic genes

Dr Gloria González-Aseguinolaza, coordinator and principal investigator for the AIPGENE project, explained how the virus was adapted to act as a gene delivery system, known as a vector.

‘Our research is mainly focused on the liver, but we know that this technology could be used for other diseases affecting other organs.’

Dr Gloria González-Aseguinolaza, Centre for Applied Medical Research, Spain

‘The virus we are using belongs to a family of viruses that affect humans, but we have replaced all the viral genes with our synthetic gene. Our gene has a specific promoter that will express this gene and the missing protein inside the liver.’

In the clinical trial, researchers gave eight patients with severe AIP the modified virus through an intravenous infusion. The main purpose of the trial was to test the safety of this approach, rather than its effectiveness.

However, the researchers were amazed by the results. Dr González-Aseguinolaza said: ‘We were looking for something, like an inflammatory reaction or some acute toxicity due to vector administration, but we didn’t find any.

‘None of the patients complained after or during the administration of the vector, so what we can really say is that it is very safe.’

Although the data collected are still being analysed, the researchers are also pleased with the improvements they have seen in the quality of life of a number of the patients they treated, which suggests that the treatment is having a beneficial effect.

Now that the AIPGENE project has demonstrated the safety of the viral vector technique, the researchers are hoping to conduct a larger-scale trial to test the treatment’s effectiveness.

Wide applications

The project’s results are significant for other rare genetic diseases in which the deficiency of a gene causes certain molecules to build up to toxic levels, as it suggests they could also be treated using virus vectors carrying new genes.

Dr González-Aseguinolaza’s research group has already started working on similar gene therapy treatments for two other rare liver diseases, Wilson’s disease and hyperoxaluria, both of which can affect very young children and currently have no cure, except liver transplantation.

They are also collaborating with other research groups. ‘Our research is mainly focused on the liver, but we know that this technology could be used for other diseases affecting other organs,’ said Dr González-Aseguinolaza.

‘We are starting to collaborate with people working in other areas, for example the heart, brain and eyes. The technology is the same, although you might have to use a different serotype (strain of virus) to target other cells.’

Dr González-Aseguinolaza said that the viral vector technology is now close to being optimised and predicted that the next product is likely to be approved in five to six years. However whether it will be people with AIP, or those who suffer from other diseases, who are next to benefit from gene therapy is yet to be seen, as other research groups are starting clinical trials on other disorders and catching up.

Gene therapy drug due this year

The very first gene therapy drug in the Western world, developed using the viral vector technique, is expected to be commercially available later this year, following its approval by the European Medicines Agency and European Commission in 2012.

The drug, alipogene tiparvovec, is a treatment for lipoprotein lipase deficiency (LPLD), a serious disorder that affects roughly one in a million people, and is administered via a series of injections.

Due to a mutation in a single gene, people with LPLD lack the enzyme lipoprotein lipase (LPL), which breaks down fatty acids. As a result, large amounts of fat build up in their blood, leading to symptoms including abdominal pain and recurrent pancreatitis.

Symptoms can start from a very young age and before the approval of alipogene tiparvovec the only treatment was a strict low-fat diet.

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