Duchenne muscular dystrophy (DMD) is the most common type of muscular dystrophy, which is characterised by muscle weakening and breakdown. It is a devastating disease that we still don’t fully understand, and currently there is no cure. Patients have a very limited number of therapy options. Scientists are working hard to develop new treatment therapies, but they still face many challenges.

Characteristics of DMD

DMD is caused by a defect dystrophin gene. Dystrophin is a protein that can be found in muscles that are attached to the skeleton, as well as in the heart and the brain. It acts like a muscular shock absorber, thereby increasing the strength of a muscle fibre. Dystrophin stabilises the muscle fibres, in particular when they contract. Without dystrophin, muscle fibres are more fragile and more prone to damages and inflammation. This chronic stress can lead to premature death of muscle fibres, which are then replaced by fat and scar tissue (fibrosis). The precise mechanisms of how the lack of dystrophin leads to loss of muscle fibres remains unclear.

DMD affects one in 3500 boys/men and a diagnosis is often made when the first symptoms appear (3–5 years of age). DMD is characterised by muscle wasting and weakness, which progresses very quickly. The symptoms of DMD may differ depending on the degree of severity. Untreated patients will usually need to use a wheelchair by the age of 12 and die in their 20s; however, with treatment many patients live to the age of 30–40 years. Most patients die due to cardiac or respiratory problems.

Approximately one-third of patients with DMD develop cognitive and behavioural problems, such as difficulties with language learning, emotional control, adapting to changing situations and decision-making.

A milder version of DMD is Becker muscular dystrophy (BMD), which affects one in 30.000 boys/men. Patients with BMD also have a defect dystrophin gene; however, it produces a shorter version of dystrophin which does have some function. Patients with BMD therefore often develop symptoms at an older age (usually 5–15) compared with those with DMD.

Genetic reasons for DMD

Dystrophin is the largest gene described in humans and, due to its length, it is highly vulnerable to mutations. Scientists have been able to categorise the most common variations of a defect dystrophin gene according to mutation type:

• Deletions (65% of DMD cases)
• Duplications (6–10% of DMD cases)
• Small mutations and rearrangement (~25% of DMD cases)
• Complex rearrangements (<2% of DMD cases)

Patients with DMD develop the disease either by inheriting a faulty gene or by developing a spontaneous mutation in the dystrophin gene during early embryonic development.

DMD in boys

Each person inherits a set of chromosomes from their father and mother. The X and the Y chromosomes are sex-determining: girls/women have two X chromosomes, and boys/men have one X and one Y chromosome. The dystrophin gene is located on the X chromosome. In contrast to boys/men, girls/women usually have two dystrophin genes and therefore if one of them has a mutation, the working gene can compensate for the defective gene. Therefore, the vast majority of patients with DMD are male. Girls/women with one defect dystrophin gene are called carriers.

DMD in female carriers

There is a small number of female carriers who develop symptoms of DMD. They are therefore called manifesting carriers.

• Every cell can only have one working X chromosome. During early development of a female embryo, each cell decides to randomly switch off one of its two X chromosomes. In a female carrier, if more than 50% of cells switch off the functioning dystrophin gene, she will develop DMD symptoms. This mechanism is called skewed X inactivation. Depending on how many cells produce dystrophin, female DMD patients may develop a mild form of the disease that progresses slowly.
• On very rare occasions, the female carrier loses her functioning dystrophin gene through a spontaneous mutation during embryonal development.

Current and future therapies for DMD

Currently there is no cure for DMD, and most available therapies provide treatment by managing the symptoms of the disease. In addition, patients with DMD usually require multiple surgeries, for example for muscle biopsies, foot surgery, insertion of a feeding tube, or to correct spinal curvature.

As standard therapy, corticosteroids are used to slow down the progression of DMD in patients from 4–6 years of age. The precise mechanisms of corticosteroids are unknown; however, they have been shown to improve the quality of life of patients due to their anti-inflammatory effects, by increasing muscle fibre strength and improving heart function. However, patients must take them every day, which is often associated with adverse effects such as weight gain, bone fractures and cataracts. The choice of corticosteroid depends on availability, costs and adverse effects.

Scientists have tried to increase the number of muscle fibres in the body with different types of therapies, such as injection of muscle or stem cells.

• Muscle cells taken from a healthy donor were unable to survive in patients with DMD, partly because the patients’ immune system recognised them as foreign cells and therefore destroyed them.
• In initial studies, the injection of stem cells resulted in successful development of muscles. Stem cells have the ability to develop into different cell types, including muscle fibres. There are two approaches for this type of therapy:
  1. Stem cells are taken from a patient with DMD, genetically altered outside of the body, and then re-implanted.
  2. Stem cells from a healthy donor are given to a patient with DMD.

It is suggested that dystrophin levels of 30–60% might preserve muscle function. Therefore, additional therapies aim to treat DMD by restoring dystrophin at a cellular level. These therapies are at different stages of drug development.

• The complete dystrophin gene is too big to be reproduced by gene therapy. However, a shortened (truncated) version of the gene has been developed that might result in BDM. Initial results were positive; however, the patient’s immune reaction can reduce the therapeutic effect.
• Read-through agents allow the production of dystrophin by ignoring any stop signals during the process. This therapy could help ~15% of patients with DMD as they do not produce dystrophin because of a stop signal.
• Upregulation of the protein utrophin to replace dystrophin has shown promising results. Utrophin has some functional differences to dystrophin and, in healthy humans, gets replaced by dystrophin in an aging However, it has been shown to be an effective dystrophin substitute in muscles.
• Skipping the gene part with the mutation (also called exon skipping) can result in an incomplete but functioning version of dystrophin. This therapy has the potential to provide a personalised, therapeutic approach. Initial studies showed promising results; however, these results still need to be confirmed in a larger patient group.
• In addition, scientists are trying to develop better ways to transport drugs to the affected muscle cells, such as with nanotechnologies. The perfect transport system should be stable, spread via circulation, reach the muscles tissues and release the drug in a controlled manner.

DMD – scientific efforts allow for hope

Within the last few years, scientists have made vital progress in understanding the mechanisms of DMD and have developed therapies that have shown initial positive results. Most of these therapies are still at early stages and require further in-depth research. Therefore, scientists still face the challenge of finding a therapy that helps all patients with DMD.

Susanne Ulm is a Medical Writer part of our Prime team at Prime Global and has been with the company since November 2014. Susanne has broad experience in different therapeutic areas, and has a passion for communicating science to different types of audiences.