Some areas in which research is being focused at the moment include:
This approach aims to skip the faulty section of the gene so that dystrophin protein can be produced, albeit in a shortened form. It is hoped that this will drastically reduce the symptoms of DMD to a severity similar to that experienced by people with Becker muscular dystrophy.
Exon skipping drugs are sometimes called ‘molecular patches’ or referred to by their technical name ‘antisense oligonucleotides’ or ‘AONs’. Molecular patches are not universally applicable to all boys with DMD because they must be specific for a patient’s particular genetic error. The dystrophin gene is made up of 79 pieces called exons, and mistakes that cause DMD can occur in any of these. Initially molecular patches are being developed that work on the parts of the gene that most often contain mutations. If these prove to be successful more exon skipping drugs will be made to target other regions of the dystrophin gene. In total it is thought that approximately 83 percent of boys with DMD may be able to be treated by exon skipping but this will require the development of more than 100 different molecular patches which could take some time.
Two similar exon skipping technologies are currently being tested in clinical trial – by the companies Sarepta Therapeutics and Prosensa (in collaboration with GSK). Their molecular patches have been given the names ‘eteplirsen’ and ‘drisapersen’ respectively and they are both designed to skip exon 51 of the dystrophin gene which could help about 13 percent of boys with DMD.
Results from the phase 2 trials of eteplirsen (Sarepta) are looking promising with dystrophin produced in the muscles and walking ability stabilised. The results should be viewed with caution though because testing has so far only occurred in a small number of patients. A phase 3 trial is now being planned.
Unfortunately a large phase 3 clinical trial of drisapersen by GSK did not prove drisapersen to be effective. This was announced in a press release on 20 September 2013. The trial tested drisapersen in 186 boys from 20 countries around the world (not Australia) for 48 weeks. Preliminary results showed that the treated boys performed no better at muscle strength tests (including the six minute walk test) than those receiving placebo. However the drug's original developer - Prosensa - has revealed that, based on more clinical trial results, it may work if boys are treated younger and for longer.
In March 2014 Prosensa released news from a smaller phase 2 trial of drisapersen which tested two different doses of the drug in 51 biys with Duchenne MD. The phase 2 trial showed that boys who received the higher dose of drisapersen (the same dose as in the phase 3 trial) experienced stabilisation and even some improvement in their muscle function as measured by the six-minute walk test after 24 weeks. They maintained this stabilisation for another 24 weeks after treatment was stopped. However, the number of boys treated was small and the results were not statistically significant. Therefore, further analysis of the results in combination with the results of the other clinical trials of drisapersen will be required.
The boys in the phase 2 trial were on average younger than those in the phase 3 trial and Prosensa is speculating that this is the reason for the conflicting results. It is not known whether boys need to be younger for the treatment to work or if the way treatment success was measured - the six minute walk test - is only reliable in younger boys.
The aim of gene therapy for DMD is to introduce a healthy synthetic copy of the dystrophin gene into the muscles so that dystrophin protein can be made. Several challenges exist with this approach.
Firstly, the dystrophin gene is too large to fit inside the virus used to deliver it to the muscles. To address this, scientists have produced a shortened version of the gene by removing non-essential parts. This shortened gene is called mini-dystrophin and it is similar to the gene that some mildly affected men with Becker MD have.
Secondly, the body may recognise the virus or the newly synthesised dystrophin protein as foreign and mount an immune response against it which would drastically reduce the effectiveness of the therapy. Indeed this is what happened in a small clinical trial testing mini-dystrophin gene therapy in boys with DMD. Research is ongoing to understand this immune response and find ways to avoid it before another clinical trial is started. Drugs that suppress the immune system may need to be given and it is also thought that the way the gene therapy is designed and administered may help to avoid an immune response.
In research published in October 2013 it was shown that it may be possible to use a technique called plasmapheresis to prevent an immune reaction during gene therapy. Plasmapheresis, which is widely used to treat patients with autoimmune disorders, involves filtering antibodies out of the blood. The antibody loss is temporary; the body begins producing new antibodies within a few hours of the procedure.
Reading through stop signals
Ataluren (previously called PTC124) is an oral drug that targets a specific type of mistake in the genetic code, called a ‘nonsense mutation’, which affects approximately 10 to 15 percent of boys with DMD. This is when a stop signal is present part way through the gene. Ataluren encourages the cell to ignore this stop signal and continue to read the full set of instructions contained within the gene. Ataluren has been tested for DMD in a phase 2b clinical trial which showed that it may be able to slow down the rate of decline in walking ability. A larger phase 3 trial is underway to confirm these results prior to applying for the drug to be approved for sale. Researchers are also investigating alternative drugs to ataluren that may be more effective at reading through stop signals, but these are not yet ready to be tested in clinical trial.
Stem cell therapy
In this procedure donor cells are injected into damaged muscle in the hope that they will fuse with the diseased muscle and create some healthy muscle fibres. Promising results have been obtained in mouse and dog models with stem cells called ‘mesangioblasts’. Mesangioblasts are stem cells found in the walls of blood vessels that under the right conditions can develop into muscle cells. Mesangioblasts have the ability to travel through the blood stream and make their way into the muscles. A clinical trial is ongoing in Italy to assess the safety of transplantation of mesangioblasts (obtained from unaffected brothers) into DMD patients. The first 6 patients have received multiple injections of mesangioblasts into an artery. It is anticipated that the results will be available late 2013.
Challenges with this approach will still need to be overcome. Transplantation of donor cells will elicit an immune response (like the transplantation of any tissue into another person). It may be possible to give drugs that suppress the immune system. This is standard treatment for individuals receiving an organ transplant. Unfortunately, chronic treatment with these drugs is not without side effects. Scientists are also working on ways in which the patient's own stem cells could be isolated, grown in the lab, the genetic defect corrected with gene therapy and transplanted back into the patient.
It is important to note that there are currently no licensed stem cell treatments for muscular dystrophy. There are clinics that offer expensive stem cell treatments but the safety and benefit has not been tested in clinical trial. This means the treatment may be ineffective and even dangerous.
Our bodies naturally make a protein similar to dystrophin called utrophin in small amounts. It is thought that utrophin may be able to compensate for the lack of dystrophin in boys with DMD. Research in mice and dogs lacking dystrophin has shown that increasing the levels of the utrophin protein can prevent muscle damage. Professor Dame Kay Davies' laboratory at the University of Oxford has been researching utrophin for more than 20 years. In recent years, in collaboration with Oxford biotechnology company Summit plc they found a promising drug - called SMT C1100 - that was able to increase the amount of utrophin in a mouse model of DMD. SMT C1100 is now in the early stages of clinical trial – it has been tested in a phase 1 trial in healthy volunteers and a phase 1b trial started in December 2013 to test the drug in 12 boys with Duchenne MD. This trial will further test the safety of the drug and determine the dose to be used in a larger trial to test if it is effective. More information is available on the Summit plc website
Reducing muscle damage
Various drugs are being investigated for their ability to treat the symptoms of DMD and slow down disease progression. In DMD the muscle fibres are continuously damaged when the muscles contract. This causes inflammation which further damages the muscles leading to muscle wasting and the accumulation of scar tissue (‘fibrosis’). Drugs are being researched that could improve the ability of the body to repair damaged muscle, suppress inflammation and inhibit scar tissue formation.
An example of this approach is a drug discovered by reseachers in the USA that could replace the corticosteroid drugs such as prednisolone currently used to treat Duchenne MD. In studies in mice the drug - called VBP15 - worked better than prednisolone without the harsh side effects. Clinical trials of VBP15 are being planned with an expected start date in 2014.
Catena®, (idebenone), an antioxidant, is in phase 3 clinical trial for Duchenne MD. Another anti-oxidant compound currently in phase 2/3 clinical trial is Sunphenon Epigallocatechin-Gallate (EGCg) which is extracted from green tea.
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