Friday 6 July 2012

Infectious delivery: using a virus to deliver molecular patches

Researchers from Oxford have shown that a virus can deliver molecular patches to the muscles and heart. A single injection of the virus into a mouse with symptoms similar to Duchenne muscular dystrophy restored dystrophin production in the muscles and heart, reduced the severity of symptoms and increased life expectancy significantly. If the delivery method can be successfully tested in clinical trials, the number of injections required to deliver molecular patches could be reduced.

what did the research show?
what does this mean for patients
further information and links

What did the research show?

Several trials are currently underway to test potential treatments for Duchenne muscular dystrophy using a technology called exon skipping. The technology uses molecular patches to let cells skip the mutation in the dystrophin gene to restore production of a shorter, but functional dystrophin protein. The aim is to reduce the severe symptoms of boys with Duchenne muscular dystrophy to the milder symptoms associated with Becker muscular dystrophy. One of the challenges of this technology is the efficient delivery of molecular patches to all muscles in the body, including the heart. In addition, the molecular patches are short lived in the body, and if the technology develops into a treatment, regular injections will likely be required.

To overcome these difficulties, Prof. Kay Davies’ group used a type of virus called Adeno-associated virus which has never been shown to cause disease in humans but has the ability to infect muscle cells. The virus used in this study was modified to carry the genetic blueprint of the molecular patches and to efficiently deliver this information into muscle and heart cells. The genetic blueprint would then lead to the production of high levels of molecular patches exactly where they were needed.

To test their theory, the team used a mouse model with symptoms similar to Duchenne muscular dystrophy. In these animals, symptoms appear at an early age and the mice experience muscle weakness and wastage. The mice also have severe curvature of the spine and eventually become immobile and have a life expectancy of six – 18 weeks compared to at least one year for healthy mice.

Following a single injection of the virus the researchers found the same levels of dystrophin in the muscles as would be seen in healthy mice. Muscle fibres in treated mice were also restored to comparable condition to healthy mice and the change in the overall condition of the mice was significant: in mice injected with the virus carrying the genetic blueprint for the molecular patches muscle strength increased, curvature of the spine was reduced and the mice survived for about one year before symptoms returned.

Most importantly, levels of dystrophin in the heart were especially high – something, the researchers say, which has challenged some methods of molecular patch delivery.

What does this mean for patients?

This research has successfully demonstrated that an Adeno-associated virus can be used to efficiently deliver molecular patches to the muscles and heart. However, this is very early research in an animal model and its potential for use in clinical practice will require further investigation. As mentioned earlier, it must also be noted that like all other exon-skipping technologies, this potential therapy would not cure Duchenne muscular dystrophy – but would reduce the severity of symptoms to a level similar to that seen in Becker muscular dystrophy.

There are, however, also disadvantages associated with this delivery method. The Adeno-associated virus provokes a mild immune response and this could prevent a second or third injection being given to the boys. However, research is currently underway to investigate the use of immune-suppression (drugs which stop the immune system working properly) to stop the body’s immune system responding to the virus. Researchers hope this might allow repeat injections to restore dystrophin production over a long period of time.

In the study the mice received only a single injection whose effects lasted almost one year. If this delivery method was successful in clinical trials, it could reduce the number of injections required to deliver molecular patches. This technique has also been shown in an animal model to be particularly good at increasing dystrophin expression in the heart, something other delivery methods might struggle to do.