A promising new treatment approach for Duchenne is focussing on a technique called “exon skipping” (you can read more about this technique here). This approach uses short pieces of DNA called antisense oligonucleotides (AOs) that allow the error in the dystrophin gene to be skipped over when the gene code is read. This causes the cell to once again produce the dystrophin protein, albeit a slightly smaller and less functional version. This approach has already been shown to restore levels of the dystrophin protein in an animal model and the first clinical trials in the UK will be underway soon to test safety and effectiveness in humans.
Mutations in lots of different places in the dystrophin gene can cause Duchenne and this is why different parts of the gene are affected in different boys. The AOs have to be designed specifically for one dystrophin mutation, or group of mutations. The clinical trial that is currently underway is focussing on mutations around exon 51. The aim is to identify the best AO to match this exon which would potentially allow about 17% of all DMD mutations to be targeted. However, there are many others that could feasibly be treated using this technique.
The current two year project has two main aims. The first one is to identify AOs for different parts of the dystrophin gene in order to target additional mutations. This will allow scientists to expand the use of the technique of “exon skipping” to a greater number of individuals with Duchenne. The second aim is to improve and optimise the methods by which the AOs are delivered to all the muscles in the body. This is done by adding different chemical molecules and groups to the AO which allow it to stay in the body for longer thus achieving a greater delivery to the muscles. Prof Dickson and Dr Wood will be investigating which molecules are most efficient for delivery of the AOs to the muscle. This is an important piece of research as better delivery of the AO means a smaller dose can be given. Generally the smaller the dose of a drug, the fewer side effects there will be.
This project adds to a growing body of research on exon skipping and could prove invaluable for future clinical trials of this technique.
Project leaders: Prof George Dickson and Dr Mathew Wood
Location: Royal Holloway University of London and University of Oxford
Duration of project: 2 years (starting September 2007)
Total Project Cost: £213,700
Official project title: Antisense oligonucleotides for therapeutic skipping of dystrophin exons: Pre-clinical and translational development of new targets and improved delivery methods.
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