Delivering therapy beyond the blood-brain barrier

June 24, 2014,

Brain diseases are particularly challenging to treat. Every substance that has to be delivered to the brain needs to overcome several obstacles, such as the blood-brain barrier—a system that prevents potentially dangerous substances, but also many drugs, to enter this organ—,to get to its target. This is true not only for drugs, but also for the viruses that many scientists think could be used as vehicles, or vectors. These would deliver functioning genes in the brain as a way to treat neurodegenerative diseases. Now, the EU-funded project BrainCAV, completed in 2013, has tried to develop and test one such vector in animals. Project coordinator Eric Kremer, director of research at the CNRS Institute of Molecular Genetics at Montpellier, in France, talks to about the strength of this approach and of its possible applications in the treatment of brain diseases.

How did you discover that the CAV-2 virus you were researching could infect neurons?

We started working with canine adenovirus type 2, or commonly referred to as CAV-2, back in 1994. CAV-2 is best known for its ability to infect the respiratory tract of dogs and give a mild cough. In the early 1990's, CAV-2 was the only nonhuman adenovirus that had been sequenced and well characterized. This was because an attenuated strain was used as a vaccine in dogs. The lab's initial idea was to use it for for cystic fibrosis. However, we serendipitously found that CAV-2 vectors were very good at infecting in the central nervous system.

Why is this virus considered a good candidate for gene therapy of brain diseases?

Humans are constantly exposed to adenoviruses. We probably have five or ten adenoviruses circulating at any given time. The idea was to use a non-human adenovirus to prevent the neutralisation of the vector by the immune response in humans. CAV-2 vector also had some other interesting characteristics. When we injected it into the brain, we found that it preferentially infected neurons. Another characteristic is that it goes to numerous brain structures via the axons that project into the site of injection. In addition, one can put several genes or expression cassettes in it. Or alternatively very big genes.

What tests have you performed on the vector?

We incubated CAV-2 vectors in cells from almost every species imaginable and injected them into the brains of mice, rats, guinea pigs, dogs, lemurs and old and new world monkeys. We also tested the vector in human brain tissues. Then we created a vector to treat a rare orphan disease, mucopolysaccharidosis type VII (MPS VII), also called Sly syndrome. This affects the entire brain. There are only a few hundred documented cases of MPS VII. But it is a member of a larger group of diseases called mucopolysaccharidoses. What we did is put a good copy of the gene affected into the vector and tested it in the brains of mice and dogs with the disease.

For what other kind of diseases could CAV-2 vectors be used?

The options are only limited by our imagination. For the brain, many of the other eleven mucopolysaccharidoses are potential targets. In parallel, we also hope to use it as a tool to understand . For example, we have tried to create a primate model of Parkinson's disease. Our idea is that with CAV-2 vectors we could infect dopaminergic neurons, which are some of the neurons affected in Parkinson's disease. We could also express mutated Parkinson's disease-related genes and induce symptoms of the disease.

What is the next step?

Our idea at the moment is to continue with mucopolysaccharidosis, in particular type VII. We hope that once we have the proof of principle showing we can treat the neuropathology and the cognitive effects associated with the disease, we will then be able to produce a vector according to so called Good Manufacturing Practices—which are regulations for the production and use of vectors as drugs—and propose it as a therapy.

Explore further: Innovative method to treat Alzheimer's in mice

Related Stories

Innovative method to treat Alzheimer's in mice

April 1, 2013
Researchers from the RIKEN Brain Science Institute report that they successfully used a virus vector to restore the expression of a brain protein and improve cognitive functions, in a mouse model of Alzheimer's disease.

Stimulating brain cells stops binge drinking, animal study finds

January 3, 2014
Researchers at the University at Buffalo have found a way to change alcohol drinking behavior in rodents, using the emerging technique of optogenetics, which uses light to stimulate neurons.

Two approaches to treat Lysosomal Storage Diseases

April 15, 2014
Enzyme therapy proves effective in treating LSDs, whilst gene therapy is an upcoming contender.

Gene therapy for lysosomal storage disease shown to be safe and well tolerated

March 11, 2014
Several young children suffering from a severe degenerative genetic disease received injections of therapeutic genes packaged within a noninfectious viral delivery vector. Safety, tolerability, and efficacy results from this ...

Common links between neurodegenerative diseases identified

April 18, 2014
The pattern of brain alterations may be similar in several different neurodegenerative diseases, which opens the door to alternative therapeutic strategies to tackle these diseases

Recommended for you

Forces from fluid in the developing lung play an essential role in organ development

January 23, 2018
It is a marvel of nature: during gestation, multiple tissue types cooperate in building the elegantly functional structures of organs, from the brain's folds to the heart's multiple chambers. A recent study by Princeton researchers ...

More surprises about blood development—and a possible lead for making lymphocytes

January 22, 2018
Hematopoietic stem cells (HSCs) have long been regarded as the granddaddy of all blood cells. After we are born, these multipotent cells give rise to all our cell lineages: lymphoid, myeloid and erythroid cells. Hematologists ...

How metal scaffolds enhance the bone healing process

January 22, 2018
A new study shows how mechanically optimized constructs known as titanium-mesh scaffolds can optimize bone regeneration. The induction of bone regeneration is of importance when treating large bone defects. As demonstrated ...

Researchers illustrate how muscle growth inhibitor is activated, could aid in treating ALS

January 19, 2018
Researchers at the University of Cincinnati (UC) College of Medicine are part of an international team that has identified how the inactive or latent form of GDF8, a signaling protein also known as myostatin responsible for ...

Bioengineered soft microfibers improve T-cell production

January 18, 2018
T cells play a key role in the body's immune response against pathogens. As a new class of therapeutic approaches, T cells are being harnessed to fight cancer, promising more precise, longer-lasting mitigation than traditional, ...

Weight flux alters molecular profile, study finds

January 17, 2018
The human body undergoes dramatic changes during even short periods of weight gain and loss, according to a study led by researchers at the Stanford University School of Medicine.


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.