Tuesday 5 January 2010

UK exon skipping clinical trial for Duchenne reports promising preliminary results

A press release from AVI Biopharma has announced initial results from the UK systemic (body wide) exon skipping clinical trial for Duchenne muscular dystrophy. The trial involves injecting different doses of a 'molecular patch' into the blood stream of boys with Duchenne muscular dystrophy. The boys are all volunteers and have been involved in testing since February 2009. In some boys there is evidence that exon skipping was successful and one boy has shown an increase in production of dystrophin protein. Another eight boys are to be given an increased dose. The researchers are hopeful that at higher doses there will be a greater production of dystrophin.

Exon skipping involves short strands of DNA, known as 'antisense oligonucleotides' (AOs) or 'molecular patches' which can restore production of the protein dystrophin (which is missing in Duchenne muscular dystrophy). Read more about how exon skipping works.

A molecular patch, called AVI-4658, is being trialled in the UK by members of the MDEX consortium led by Prof. Francesco Muntoni. This phase of the trial is jointly funded by an award to Prof. Muntoni from the MRC (Medical Research Council) UK in partnership with the sponsor AVI-BioPharma. The Muscular Dystrophy Campaign played a key role in setting up the MDEX consortium and was instrumental in securing £2 million from the Big Lottery Fund and the Department of Health for the early phase of this clinical trial. Important pre-clinical development of this treatment approach was also supported by the charity and we currently fund research in the laboratory of Prof. Dame Kay Davies to further optimise the technology.

AVI-4658 is designed to bind to a particular region in the dystrophin gene (exon 51) and could potentially be used to treat the 13% of boys with Duchenne who have a mutation in this region. The first phase of testing this molecular patch in patients was completed in December 2008. In this trial seven boys had AVI-4658 injected into a muscle in one of their feet. The next step is to develop a way to effectively deliver the molecular patch to all of the muscles of the body so the current clinical trial which started in February 2009, is testing injection of the molecular patch into the bloodstream.

What has the clinical trial shown?

Nineteen boys with Duchenne muscular dystrophy between the ages of 5 and 15 were recruited for the study from Great Ormond Street Hospital in London and Royal Victoria Infirmary in Newcastle. The boys were divided into six groups, with each group receiving a different dose of AVI-4658 injected into a vein, once a week, for 12 weeks. Dose was calculated based on body weight (0.5, 1, 2, 4, 10 and 20 mg/kg). The trial is a 'dose escalation study' which means that they inject the group of boys receiving the lowest dose first (0.5 mg/kg), and if this proves to be safe, they give it to the group receiving the 1 mg/kg dose, and so on up to the highest dose of 20 mg/kg. A biopsy of the bicep muscle of the upper arm was taken before and after completion of the trial to look for dystrophin production.

So far, nine boys receiving the first four doses have completed the trial, and AVI-4658 has been very well tolerated by them. For the two lowest doses (0.5 and 1 mg/kg) however, no evidence of the molecular patch acting on the dystrophin gene was found and dystrophin protein production was not detected.

For the two boys receiving 2 mg/kg and one receiving the 4 mg/kg dose of AVI-4658 the results were more encouraging. In the biopsies from these 3 boys, researchers were able to detect evidence of the molecular patch causing exon skipping in the dystrophin gene. Some dystrophin protein production was also seen in the biopsy from one boy in the 2 mg/kg group. In this sample 21% of muscle fibres were found to have dystrophin protein. The amount of dystrophin in these muscle fibres was calculated to be 37% of normal muscle fibres.

One more boy in the 4 mg/kg group had to withdraw from the study due to a heart problem which was deemed to be unrelated to administration of the molecular patch. Another boy has since started treatment with 4 mg/kg but the results are not available yet. Eight more boys have started the trial in the 10 and 20 mg/kg dose groups.

What does this mean for patients?

Researchers don't know yet how much dystrophin protein is required in muscle cells to halt or slow the progression of symptoms for boys with Duchenne muscular dystrophy. We look forward to hearing the full results of this trial after it is completed later this year. The full results will give us a clearer picture of the potential of this new treatment.

Prof. Francesco Muntoni, Head of the Dubowitz Neuromuscular Centre, London and the trial's lead investigator said:

I am very encouraged by the evidence of accurate skipping of exon 51 in three treated patients. These results suggest that we are on the right path towards developing a drug that could play a role in the treatment of Duchenne muscular dystrophy. The fact that one patient at the 2 mg/kg dose showed significant expression of dystrophin protein leads us to expect greater levels of dystrophin expression following treatment with the higher doses of 10.0 mg/kg and 20.0 mg/kg of AVI-4658, which are currently underway in the trial.

This study used a molecular patch to 'skip' exon 51 which would be applicable to approximately 13% of boys with Duchenne muscular dystrophy. Molecular patches are very specific and have to be designed for particular mutations. Although only a small subset of mutations are addressed using AVI-4658 it is important for the researchers to use this as an example to understand whether the technology is safe and works in principle. Once this is achieved other molecular patches will follow and researchers are already developing molecular patches in the laboratory for other mutations.

Background informaton

Duchenne muscular dystrophy is caused by mutations in the dystrophin gene. This gene contains the instructions for the dystrophin protein which normally sits in the membrane that surrounds muscle fibres and protects them from damage during muscle contraction. Consequently, in Duchenne muscular dystrophy, the muscle fibre membranes become damaged and eventually the muscle fibres die.

Exon skipping, or molecular patch therapy aims to encourage the cellular machinery to 'skip over' the part of the dystrophin gene that contains the mutation. Small pieces of DNA called antisense oligonucleotides (AOs) or 'molecular patches' are used to mask the part of the gene that you want to skip, so that it is ignored during protein production. This allows the muscle to produce a shorter, but functional dystrophin protein.

About the MDEX Consortium

The MDEX consortium led by Professor Muntoni, is a mutlidisciplinary enterprise to promote translational research into muscular dystrophies, and is formed by the clinical groups of Professor Francesco Muntoni (Imperial College London and UCL Institute of Child Health) and Professor Kate Bushby and Professor Volker Straub (Newcastle University), and scientists from Imperial College London (Professor Dominic Wells), UCL Institute of Child Health (Dr Jennifer Morgan), Royal Holloway University of London (Professor George Dickson), Oxford University (Dr Matthew Wood) and University of Western Australia (Prof Steve Wilton). In addition, the charities Muscular Dystrophy Campaign (MDC), Action Duchenne and Duchenne Family Support Group also participate in the Consortium. For more information visit www.mdex.org.uk.

Further information and links

Read the AVI Biopharma press release

More information about how exon skipping works is available in our FAQ.

Read more about Duchenne muscular dystrophy.

More exon skipping news:

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Tags: Duchenne muscular dystrophy, Research Panel, Research news