Becker muscular dystrophy is a muscle wasting condition affecting, in nearly all cases, only boys or young men. It is a genetic condition that can be passed down from the parents but can also spontaneously appear without a previous family history.
Even though it is caused by mutations in the same gene as Duchenne muscular dystrophy the symptoms are usually milder because of the type of mutation. Finding and characterising the type of mutations has brought vital insight into the underlying biology of both conditions. This knowledge has been crucial for the development of therapeutic approaches.
The average age of diagnosis of Becker muscular dystrophy is eleven and walking ability is usually lost between the ages of 40 and 60. Life expectancy is often reduced, but there is a wide variation in the severity of the condition. This ranges from individuals needing a heart transplant in their teenage years to individuals that are able to pursue sports in their sixties. Cardiomyopathy is the cause of death in around half of Becker muscular dystrophy patients.
For both Becker and Duchenne muscular dystrophy there are thought to be about 2,400 affected individuals in the UK.
Becker muscular dystrophy is caused by mutations in the gene that carries the information for a large muscle protein called dystrophin. The gene retains some function and a shorter but working dystrophin protein is produced.
Dystrophin protein plays a number of vital roles in muscle. It interacts with many other muscle proteins, so that muscle fibres are strongly held together and the muscle contraction is effective. Dystrophin also acts as a shock absorber during movement thereby preventing muscle damage. By interacting with certain proteins, dystrophin has a role in increasing the blood flow to muscle during exercise. In the absence of full-length dystrophin protein, muscle breaks down and wastes away. The muscle damage caused when dystrophin is not fully functional cannot be repaired and muscle is eventually replaced by scar and fat tissue. The severity of the condition depends on how much of the dystrophin protein is missing and also on which regions of the protein the mutations affect.
Becker and Duchenne muscular dystrophy are two of the most studied muscle-wasting conditions. However the function of the dystrophin protein is not yet fully understood. There are several animal models available that have been invaluable in investigating the biology of these two conditions.
The interventions offered as the condition progresses include supportive care, physiotherapy, ventilation for respiratory failure and medications to counter heart problems. Steroid treatment is not normally used because it is thought that the benefits would not outweigh the side effects, which can be serious including weight gain, mood changes and bone thinning.
A number of promising therapeutic approaches addressing the underlying genetic cause of the condition are currently being developed as discussed below.
This approach is based on the use of a harmless virus called adeno-associated virus (AAV), which has been shown to effectively deliver genes to a range of different types of cells and tissues including muscle. The virus triggers a relatively mild immune response, which could allow it to be given more than once. One of the challenges is that the dystrophin gene is too big for the virus to carry.
Correction of mutations in patient cells could be achieved using genome editing. This is an exciting, rapidly moving field of research where enzymes are used that act as DNA scissors to cut the dystrophin gene at specific locations. The repair that results can be driven to completely mend the dystrophin gene to restore production of a full-length dystrophin protein. There is the potential to use these DNA scissors directly in patients, but this will require a lot of research and optimisation first. The attraction of gene editing as a therapy is that it could be a one-off treatment and has the potential to treat all people with Becker muscular dystrophy, regardless of their mutation. You can read more about genome editing in our feature article.
This approach is still in its infancy and a lot of preclinical research needs to be carried before clinical trials can be considered.
Developing utrophin up-regulators
Another potential therapy is to raise the levels of utrophin protein, as a functional substitute for dystrophin. Compounds that are able to do this are referred to as utrophin up-regulators or utrophin modulators. This approach has been developed in the laboratory of Professor Dame Kay Davies in Oxford, who we have funded for over 25 years. She is also the co-founder of Summit Therapeutics.
Although this approach is currently in phase II clinical trial for people with Duchenne muscular dystrophy (see Summit’s website for more information), it has the potential to also benefit those with Becker muscular dystrophy. Once Summit has shown that it benefits those with Duchenne muscular dystrophy, it plans to test the therapy in people with Becker muscular dystrophy.
There is also considerable effort ongoing in Oxford to develop second-generation compounds that have the potential to raise utrophin levels further (click here for more info).
The charity has supported high-quality research into Becker and Duchenne muscular dystrophy for many years. This has made a considerable fundamental contribution to the technologies that are currently being tested in clinical trial and to recent research advances. However these are first generation treatments and therefore might only have a moderate impact. This is the reason why there is a need to continue to support high quality preclinical research to improve existing technologies.
We support research into a novel gene therapy that would allow delivery of the full length dystrophin gene to muscle cells. In this project the researchers will use two or three viruses each carrying a different part of the dystrophin gene. In the muscle cell the different parts assemble to form the blueprint to produce a full size dystrophin protein. If successful this approach could be used to treat people with Becker as well as people with Duchenne muscular dystrophy.
Professor George Dickson and his team have developed an innovative technique with the potential to repair the genetic mutation that causes Becker and Duchenne muscular dystrophy. The ground-breaking technique, described as an application of genome editing, could be the first therapy that offers permanent correction of the genetic mutation in a person’s own DNA. Although Prof Dickson and his team are testing the technique in a mouse model of Duchenne muscular dystrophy, the learnings from this project will be important for future Becker research.
The charity has supported the group of Professor Dame Kay Davies at the University of Oxford for more than 25 years for the development of a treatment for Becker and Duchenne based on utrophin up-regulation (see above). Her laboratory identified a first compound, SMT C1100 (Ezutromid) that has been shown to raise the levels of utrophin in mouse models and is now in phase II clinical trial.
We are currently supporting Professor Kay Davies and Professor Angela Russell to develop more efficient follow-up compounds and to investigate the molecular mechanism of action. A better understanding of how these drugs work will be vital for optimising existing drugs and to identify new therapeutic targets. We have also recently awarded a new grant to Professor Davies to identify biomarkers that can be used to monitor the effectiveness of utrophin up-regulators.
There are currently a few clinical studies testing potential treatments for Becker muscular dystrophy (see below). Many clinical trials focussed on Duchenne muscular dystrophy may also have important learnings for Becker.
- Cardioprotective therapy
Beta-blockers reduce the force at which the heart beats and slow the heart rate, therefore reducing the workload on the heart. ACE inhibitors reduce blood pressure, which in turn puts less strain on the heart. Although these drugs are often used to treat the heart problems associated with Duchenne and Becker muscular dystrophy, there are no clear recommendations on when patients should begin this sort of treatment. A recent phase 3 trial in Brazil has shown that it could be beneficial for people with Duchenne and Becker muscular dystrophy to be treated with ACE inhibitors before heart weakness is detected (read our news story for more information).
- The effect of Coenzyme Q10 and Lisinopril on the heart
This study aims to test whether Coenzyme Q10 and Lisinopril can be used to prevent or slow down heart problems associated with different muscular dystrophies, including Becker muscular dystrophy. Lisinopril is an ACE inhibitor, which acts by helping to reduce blood pressure. Coenzyme Q10 is a natural antioxidant that is involved in the process of energy production by the mitochondria inside our cells. This phase II/III trial is taking place in the US, Canada and Japan and is enrolling participants by invitation only.
Clinicaltrials.gov identifier: NCT01126697
This phase I/II study is investigating whether a naturally-occurring anti-oxidant called epicatechin could improve the muscle strength of 10 adults with Becker muscular dystrophy. It is taking place in the US and is currently recruiting participants.
Clinicaltrials.gov identifier: NCT01856868