Bringing treatments into clinical practice
Since the beginning of the 1990s when DNA technology made a huge leap forward with the introduction of new techniques, more than 100 genes have been found that can cause muscular dystrophy or a related neuromuscular condition. The knowledge has been vital in enabling researchers and clinicians to classify the conditions in more detail and has led to huge improvements in the ability to give people a quicker and more precise diagnosis. But just as importantly, understanding muscle function and the biological processes that can lead to muscle disease has given researchers the tools to develop ways to treat the diseases.
For many muscle and nerve conditions, promising technologies are currently being tested in clinical trial. Although this is not a guarantee that a treatment will soon be available, it is good news that pharmaceutical companies and other funding organisations believe that these technologies are so promising that they are prepared to invest the money to carry out the clinical studies. Below is a summary of some of these new developments. You can find lots more information on these and many other trials for more conditions on our website in the Research news and Clinical trials sections.
The first gene known to cause a muscle-wasting condition was found in 1987. Researchers discovered that mutations in the dystrophin gene can cause Duchenne muscular dystrophy. It comes as no surprise, therefore, that Duchenne muscular dystrophy is the condition for which potential treatments were first developed. The most advanced and currently most promising development is a technology called exon skipping. It involves small pieces of DNA called "molecular patches", which mask the portion of the dystrophin gene where there is a mutation and restores dystrophin production. Exon skipping is a personalised medicine - the molecular patch needs to be tailored to the specific mutation in the dystrophin gene.
Clinical trials have been carried out both by a group of British scientists, the MDEX consortium, in collaboration with the pharmaceutical company AVI Biopharma and by the Dutch company Prosensa in collaboration with GlaxoSmithKline (GSK). In order to gather evidence of how well this might work, both collaborative groups have been using a molecular patch to skip exon 51. If successful, this could be used to treat about 13 percent of boys with Duchenne muscular dystrophy. I am often asked whether both companies are testing the same thing: the answer is no. To deliver the molecular patches safely and efficiently to the muscles and the heart, they have to be linked to a chemical compound. And here lies the difference - the two companies are using different chemical compounds and at the moment we do not know which one will work best.
The published results of the clinical trials completed so far show that both types of molecular patches are safe and result in the production of dystrophin. But both groups found that the amount of dystrophin produced seems to vary between different boys. Prosensa/GSK are currently conducting a large international phase 3 clinical trial involving more than 200 boys to investigate how well the molecular patch improves muscle function. The expected end date of this study is December 2012, but all boys that have participated will be entering into an extension trial lasting a further 48 months to study the long-term benefits. Prosensa and GSK's efforts, however, are not limited to exon 51. The companies have started a clinical trial to test molecular patches for exon 44 and have molecular patches for exons 45, 52, 53 and 55 in pre-clinical development. These could be used potentially to treat a further 25 percent of boys.
A lot of effort has gone into developing this technology and it would be a great advantage if this could be used potentially to treat other conditions as well. And the good news is that researchers are already looking at using this technology in different ways to treat other diseases. Researchers have already carried out experiments in animal models for myotonic dystrophy (DM1). The results of these experiments have been promising and Prosensa/GSK are now developing this technology further to test how well it works in individuals with myotonic dystrophy.
For spinal muscular atrophy (SMA), results of recent experiments have also been positive, although they suggested that in animals there is only a short window of time after birth when the technology works best. Isis Pharmaceuticals, a USA-based biotechnology company, started a phase 1 clinical trial at the beginning of this year to test the safety and tolerability of a molecular patch for children with SMA. The condition is caused by a mutation in a gene called 'survival motor neuron 1' (SMN1), which is crucial for the survival of motor neurons - the nerves that control muscle movement. No SMN protein is produced in individuals with SMA. Every person, however, has a second copy of the gene called SMN2, but the gene does not produce sufficient SMN protein to compensate for the lack of SMN normally produced by SMN1. In the case of SMA, the molecular patch has been developed with the aim of increasing the levels of SMN protein produced from the SMN2 gene.
There are numerous other clinical trials testing a variety of drugs. The Oxford-based company, Summit Corporation plc, has announced the start of a phase 1 clinical trial to test a drug - SMT C1100 - to raise the levels of utrophin in boys with Duchenne muscular dystrophy. In animal models it was shown that utrophin can compensate for the lack of dystrophin, but only if produced at sufficiently high levels. A previous phase 1 study in healthy volunteers carried out by the pharmaceutical company Biomarin failed to show that the drug reached the muscles in high enough concentrations. Summit Corporation plc has since reformulated the drug into a form that should be better absorbed and it is hoped that this new formulation reaches the muscles at levels high enough to increase utrophin levels. Muscular Dystrophy Campaign-funded researcher, Professor Dame Kay Davies has been working for more than 25 years to develop this potential treatment, which might also be used for boys with Becker muscular dystrophy.
In April, USA-based pharmaceutical company, Repligen, announced positive results from a phase 1 clinical trial of their drug RG3039. The drug had shown promise in a mouse model of SMA - the mice had an increased lifespan and symptoms typical to SMA were partially relieved. Different doses were tested in healthy volunteers and the study showed that all dose levels were well-tolerated with no serious side effects.
The Swiss-based company, Santhera pharmaceutical, has also announced the start of a phase 1 clinical trial. They hope to recruit participants in the second half of 2012 to test their drug Omigapil in patients with Ullrich congenital muscular dystrophy, Bethlem myopathy and merosin-deficient congenital muscular dystrophy (MDC1A). In animal models, Omigapil was shown to reduce muscle cell death, protect muscle tissue and the muscles were healthier with less damage than was detected in the untreated animals. The clinical trial was made possible through collaboration with EndoStem, a Europe-wide consortium of clinicians, scientists, biotech and pharmaceutical companies. One of two centres where the trial will take place is Great Ormond Street Hospital, London, under the leadership of Professor Francesco Muntoni. The Muscular Dystrophy Campaign gave vital support for this trial by funding a clinical fellow and a clinical trial co-ordinator to develop the clinical trial protocol and to help with the huge administration a trial involves.
I hope I have given you some insight into the exciting developments that are currently underway here in the UK and in other countries. Hundreds of studies are currently being carried out to test new technologies not only to address the genetic mutations leading to the different forms of muscle disease, but also to help with the symptoms. In the coming years, we will gain a better understanding of how well these new treatments might work and whether the hopes of our families have been realised. With your help, the Muscular Dystrophy Campaign remains committed to invest in research until these treatments and cures are found.