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20 June 2014

Picking the right virus candidate for gene therapy

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A promising new approach to gene therapy for neurodegenerative diseases makes use of an unexpected virus as the agent of delivery. 

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 loaded with good copies of malfunctioning genes - and delivered to cells. This is difficult but even more so is penetrating the fortress of the brain. But this is exactly what gene therapy research into central nervous system diseases aims to do. Success may depend on the choice of the Trojan horse, its size, shape, and ability to move beyond the place where it has been delivered. There is a lot of expectation that such vectors will one day be injected directly into the brain to treat several diseases. But researchers are still struggling to find the right candidates. 

Now, the EU-funded project BrainCAV, completed in 2013, may have identified a viral vector that might be very good for treating a variety of different pathologies that affect the brain. Research initially focused on gene therapy with canine adenovirus-2 (CAV-2), a virus that infects the dog respiratory tract. But almost by chance project researchers found out that this virus is very good at infecting the central nervous system of people. “We serendipitously found that CAV-2 vectors were very good at infecting neurons in the central nervous system,” says project coordinator Eric Kremer, director of research at the CNRS Institute of Molecular Genetics at Montpellier, in France.

In general, several types of viruses could potentially be vectors for gene therapy in brain diseases. These include adenoviruses, adeno-associated viruses and lentivirus. Each has its own advantages and drawbacks. Being a virus that normally does not infect humans, CAV-2 is not knocked down by our immune system. What is more, it also was discovered that CAV-2 preferentially infects neurons, not other types of brain cells. And that it has the ability to travel along the axons, the projections of neurons. So it can reach areas of the brain quite distant from the point of injection. All together, these characteristics made it an interesting candidate for gene therapy of neurodegenerative diseases.

To obtain a proof of principle that it was possible to create a therapeutic vector from the virus, scientists involved in the project tested this approach in an extremely rare disease, called mucopolysaccaridosis type VII, also known as Sly disease. The researchers inserted a functional copy of the gene affected in the disease into the virus. They then tested the vector in mice and dogs with the pathology. “We cleared the brain of all the animals from the neuropathology, and in the mice we also succeeded in preventing or reversing its cognitive effects,” Kremer tells 

Project researchers also generated a primate model of Parkinson’s disease. They delivered the CAV-2 vector loaded with a gene that causes a familiar form of the disease into the brain of monkeys. The reasoning is that if this works, the inverse process of loading the same vector with therapeutic genes will become viable.

But there are challenges regarding the production of vectors - should they demonstrate their efficacy as a treatment. A large-scale vector production according to the so-called Good Manufacturing Practices (GMP) rules, to make it fit to be used as a drug, is costly and technically challenging. The project also tackled this aspect. So, in the next few years, researchers hope to be able to produce a gene therapy for Sly syndrome. If it works, it could pave the way for testing the vector in other kind of disorders, including Parkinson’s disease.

Currently, a popular approach in gene therapy for brain diseases is with some adeno-associated viruses. A few years ago, it was discovered that they can cross the blood brain barrier when injected intravenously. And that they achieve very widespread gene delivery into the brain. When compared against this approach, one expert believes the project’s CAV-2 approach could have a possible advantage in terms of safety. One possible good trait of vectors such as CAV-2 is that they do not integrate into cells DNA. “For this reason they are considered safer than integrating lentiviral vectors,” says Angela Gritti, group leader of research on gene and cells therapy for lysosomal storage diseases at the San Raffaele Hospital in Milan, Italy. But they might not have widespread applicability in the brain. “On the other hand, they might be less suitable for global brain diseases, where the genetic error affects each and every cell,” she tells

Another expert sees an advantage of CAV-2 vector over other ones in its ability to carry a larger amount of genetic material. “These [other] vectors can carry only around five thousand base pairs of DNA. So they cannot deliver big genes,” says Simon Waddington, who leads the gene transfer technology group at University College London, in the UK. “In contrast, CAV vectors have a much larger capacity, “he tells, “And this means that they can be used to deliver any gene.” provides its content to all media free of charge. We would appreciate if you could acknowledge as the source of the content.