making muscle wasting history

Dr. Matthew Wood reports on recent developments in exon skipping trials from the Oligonucleotide Therapeutic Society meeting held in Fukuoka, Japan in November.

Last week I attended the Oligonucleotide Therapeutic Society (OTS) meeting which was held in Fukuoka, Japan. The OTS has been convening regularly over the last six years to discuss the latest developments in the use of oligonucleotide treatments for many different diseases including DMD. Without doubt, the recent developments in exon skipping treatments for DMD is the most exciting thing to happen during this time. For this reason a special session on exon skipping oligonucleotide therapies for DMD was organised. This is the first time that DMD has been the focus in this way.

Treatments for DMD are leading the way in this type of new medicine, and as the treatments develop participants within the Society expect to learn a lot about how they can be used for other diseases. The meeting attracted leading groups working on exon skipping from around the world.

Ryszard Kole from AVI Biopharma reported on the latest developments in the AVI sponsored exon 51 clinical trial in the UK, where the final group of boys are now being recruited and treated. No adverse or unexpected events have been found which is important as it suggests that high doses of PMO are very likely to be well tolerated by the boys. Results of this trial should be known early in 2010.

Annemieke Aartsma-Rus from Leiden gave the latest update from Prosensa on their recently completed exon 51 systemic trial. In this study the oligonucleotide was administered by subcutaneous injections and went to a maximum dose of 6mg/kg which was well tolerated. At all doses tested dystrophin exon skipping was detected in a single muscle following biopsy. The biopsy also showed evidence of dystrophin protein production in the muscle. It remains unclear how much dystrophin protein was produced, and whether this resulted in any improvement in the boys’ condition. This study is continuing and further information is awaited.

Professor Matsuo from Kobe, Japan talked about progress in clinical trials in Japan. His group was one of the first to demonstrate dystrophin exon skipping in the 1990s in the lab and was also the very first team to carry out a clinical trial in humans. His group has now treated a number of patients that require exon 19 skipping. Due to the small number of patients it is not clear to what extent the treatment is having any benefit. Nevertheless the DMD community and healthcare system in Japan is highly organised and there are opportunities for extending the European clinical trials to Japan for exon 51 and other exons.
I spoke about new ways to improve the delivery and effectivenss of exon skipping oligonucleotides by using second generation so-called peptide PMOs. I discussed the work we are doing in Oxford and with Mike Gait in Cambridge in which new peptides have been discovered that dramatically improve the effectiveness of oligonucleotides in muscle and also in the heart at lower doses. We are now progressing this work in partnership with AVI Biopharma, supported by funding from Action Duchenne.

Steve Wilton rounded off the meeting by talking about other major issues that need to be addressed in order to rapidly extend exon skipping therapies to all DMD patients. He talked about exons beyond exon 51 and talked about the development of oligonucleotides for the skipping of these other exons. He also talked about the time needed to do this and suggested that short-cuts could and should be achieved by developing methods for multiple exon skipping and fast-tracking of new exon therapies into clinical trials once proof-of-principle has been obtained for exon 51. Regulatory authorities in Europe and America are likely to be supportive of this approach.

A very lively discussion followed chaired by Mike Gait. Participants highlighted the importance of the exon 51 trials and that these are safe and effective, as this will permit not just other exons to be targeted in rapid, shortened trials, but also studies on other diseases to be started. They highlighted the importance of ensuring that the heart and other organs affected by DMD are also effectively treated as well as muscles. They also discussed the importance of the peptide PMO work, which, if it can be proved to be safe and effective, will open up the possibilities for achieving high level dystrophin correction and also achieving correction in tissues other than muscle. The other main point discussed was the need for companies like AVI and Prosensa to work with health services to ensure that the costs of oligonucleotide treatments will be affordable.

Given the clinical trials that are currently taking place, in six months time when the trials are completed we should have a much better understanding of how successful this type of treatment will be. We may not get all the results we hope for, but whatever the outcome, it will help us to work out where to focus our efforts in order to turn these promising therapies into a realistic medicine for DMD.

Dr Matthew Wood is a Lecturer in Biomedical Science in the Department of Physiology, Anatomy and Genetics, University of Oxford.