Renewed hope for gene therapy in rare disease

July 2, 2014
Renewed hope for gene therapy in rare disease

Between 30 and 40 million people in Europe suffer from rare diseases—many of them children. As most of these diseases have genetic origins, gene therapy is a major hope for their future cure. Until now, however, there have been very few successful trials. Now, the EU-funded project AIPGENE, due to be completed in 2014, may have made significant progress in a gene therapy approach.

The project focussed on the genetic liver disorder, Acute Intermittent Porphyria (AIP). Through an early stage clinical trial, in phase I, it demonstrated the viability of a new approach, based on a so-called, adeno-associated vector (AAV). This is a 'DNA transporter' derived from a type of virus and carries the therapeutic gene to liver cells, known as hepatocytes.  

"If we are able to correct enough hepatocytes and give them the gene that has not been expressed in those hepatocytes, we will not only be able to treat Porphyria, but also many other diseases in which the target organ is the liver," says project coordinator Gloria González-Aseguinolaza, who is also director of the and regulation of gene expression programme at the Centre for Applied Medical Research (CIMA) at the University of Navarra, in Spain. This brings renewed hope for the viability of gene therapy to cure rare genetic diseases.

Gene therapy exploits modified viruses, such as AAVs, as carriers of therapeutic genes. So the less likely the virus is likely to bring illnesses to humans, the easier it is to succeed in a clinical trial. It is particularly suited for disorders where only one organ is affected. And where the correction of a single gene can reduce the effect of the disease or even heal it. 

Unfortunately, there can be side effects. In previous studies of treatment of Haemophilia B, for example, researchers used what is referred to as an AAV serotype 8 (AAV8).  But scientists found that there was an increase in, so-called, transaminases, which indicates liver injury. Although they were cured, patients had to receive immunosuppressive treatment.

In the Porphyria trial, the patients did not suffer these side effects. "We used an AAV serotype 5 (AAV5).  Because we observed from animal models that this serotype has a strong liver tropism," González-Aseguinolaza tells This means that AAV5 seems to be more liver specific and not as commonly used as AAV8.

One expert sees an advantage in administering the therapeutic gene through AAV5. "Serotype 5 can be used in those people who developed antibodies against [serotype] 8 and also in the cases when the therapeutic gene has to be re-administered after 10 or 20 years. For example in people with AAV8 who have by then developed antibodies against it," says Carlo Viscomi, a senior investigating scientist at the Mitochondrial Biology Unit of the Medical Research Council in Cambridge, in the UK, and at the Molecular Neurogenetics Unit of the Carlo Besta Neurological Institute, in Milan Italy.

Indeed, a large percentage of the population has encountered these viruses, usually in childhood. And their body created antibodies against them. Another expert concurs with the first. "These antibodies prevent the virus from entering your target cells. This means that if we inject the virus into the vein, for example, there are antibodies around, which neutralise it. So it does not get in and it has no effect," says Etiena Basner-Tschakarjan, senior scientist at the Center for Cellular and Molecular Therapeutics of the Children's Hospital of Philadelphia, Pennsylvania, USA. In fact, 50% of the population has antibodies against AAV8, due to having been in contact with the natural virus.

Further challenges still lie ahead. One major problem is how to reach enough cells in the organ to correct the disease. "This is very difficult as it requires strong technology to improve both the production of the vector and its efficacy to enter the cells," adds González-Aseguinolaza.

One additional problem is that "once the virus has reached its target, in some organs there seems to be a cellular response. And the cells that were successfully treated are destroyed," Basner-Tschakarjan tells, concluding: "Therefore, the positive effect at the beginning goes away."

Explore further: Picking the right virus candidate for gene therapy

Related Stories

Picking the right virus candidate for gene therapy

June 24, 2014
Viruses often get bad press. Likened to Trojan horses they are often associated with disease. But, it is precisely because of their infectious nature that they can potentially be used as gene vectors - which are vehicles ...

Empty decoys divert antibodies from neutralizing gene therapy in cell, animal studies

July 17, 2013
Gene therapy researchers have produced a bioengineered decoy that fools the immune system and prevents it from mistakenly defeating the benefits delivered by a corrective gene. The decoy was effective in animal studies, and ...

Researchers identify way to increase gene therapy success

October 30, 2013
Scientists in The Research Institute at Nationwide Children's Hospital have found a way to overcome one of the biggest obstacles to using viruses to deliver therapeutic genes: how to keep the immune system from neutralizing ...

Finding and treating the cause of inherited blindness

June 20, 2013
European scientists have made a major breakthrough in the treatment of inherited retinal diseases.

Scientists find potential new use for cancer drug in gene therapy for blood disorders

June 26, 2014
Scientists working to make gene therapy a reality have solved a major hurdle: how to bypass a blood stem cell's natural defenses and efficiently insert disease-fighting genes into the cell's genome.

Recommended for you

Scientists provide insight into genetic basis of neuropsychiatric disorders

July 21, 2017
A study by scientists at the Children's Medical Center Research Institute at UT Southwestern (CRI) is providing insight into the genetic basis of neuropsychiatric disorders. In this research, the first mouse model of a mutation ...

Scientists identify new way cells turn off genes

July 19, 2017
Cells have more than one trick up their sleeve for controlling certain genes that regulate fetal growth and development.

South Asian genomes could be boon for disease research, scientists say

July 18, 2017
The Indian subcontinent's massive population is nearing 1.5 billion according to recent accounts. But that population is far from monolithic; it's made up of nearly 5,000 well-defined sub-groups, making the region one of ...

Mutant yeast reveals details of the aberrant genomic machinery of children's high-grade gliomas

July 18, 2017
St. Jude Children's Research Hospital biologists have used engineered yeast cells to discover how a mutation that is frequently found in pediatric brain tumor high-grade glioma triggers a cascade of genomic malfunctions.

Late-breaking mutations may play an important role in autism

July 17, 2017
A study of nearly 6,000 families, combining three genetic sequencing technologies, finds that mutations that occur after conception play an important role in autism. A team led by investigators at Boston Children's Hospital ...

Newly discovered gene variants link innate immunity and Alzheimer's disease

July 17, 2017
Three new gene variants, found in a genome wide association study of Alzheimer's disease (AD), point to the brain's immune cells in the onset of the disorder. These genes encode three proteins that are found in microglia, ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.