Duchenne Muscular Dystrophy: Need for Treatment and Cure

Duchenne muscular dystrophy

Duchenne muscular dystrophy is the most common form of muscular dystrophy. It is a sex-linked disorder residing on the X chromosome. It affects primarily boys and men and is always lethal. There are few treatments to this disorder that affects 1 in every 3500 to 5000 boys born. There are no cures and few treatments for this disorder.

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Duchenne muscular dystrophy was first described by the French neurologist Guillaume Benjamin Amand Duchenne in the 1860s. Becker muscular dystrophy is named after the German doctor Peter Emil Becker who first described this variant of DMD in the 1950s. in DMD it first appears in early childhood, first manifesting when the child is attempting to learn to walk. They tend to lose the ability to walk between the ages of seven and twelve.

In Becker, it often isn’t diagnosed until adolescence or even adulthood. Its progression is much slower but by their 40s has the same result-heart failure and death. While there is no cure for either disorder, there are a few treatments available to slow the progression. Braces to support the ankle and foot or even extend over the knee are sometimes prescribed for night wear to help keep the Achilles tendon stretched.

Standing for a few hours every day promotes better circulation, healthier bones, and a straight spine. To assist with this, a standing walker or standing frame can assist these people to stand. Then to help with mobility these patients with either form of DMD end up in a wheelchair. At that point, mechanical lifts, shower chairs, and electric beds may be used. Muscular Dystrophy Association can assist those who call. They can provide information and often can assist with access to help with the equipment needed to help these boys have the best quality of life possible. The Muscular Dystrophy Association has a website to provide families with resources and ways to procure needed equipment as it becomes needed.

They also help to cover research into many neuromuscular diseases like Amyotrophic Lateral Sclerosis (ALS), Charcot-Marie-Tooth disease, and Myasthenia gravis (MDA, 2011, 2018).

Presently available treatment

Duchenne muscular dystrophy is a severely progressive, X-linked recessive neuromuscular disorder. It is caused by a mutation in the dystrophin gene resulting in absent or insufficient functional dystrophin protein. It presents as progressive muscle weakness with symptom onset between three and five years. This disease affects mostly boys and men but in rare cases, it can affect girls and women. As for care, it has been mostly a supportive one until recent modifications have been recommended to manage and treat the multiple side effects and toxicities of steroids-usual first line of treatment. With a progression of technology has come an increase in options for respiratory treatment.

It now includes a cough assist device that gradually applies positive air pressure to the airway and then shifts rapidly to negative air pressure. This uses the resulting high exhalation flow that simulates a deep natural cough. It can be either applied directly to a tracheostomy or can be used with a mask for patients not intubated. For nighttime, there is non-invasive ventilation that can assist the DMD patient at night to be able to breathe more efficiently while sleeping. And while these are all very useful in increasing their quality of care, new research is needed to not just validate the current treatment being utilized but validate the earlier use of them to prolong the patients’ quality of life (McDonald & Mercuri, 2018).

Further research needed
This disease causes a marked striated muscle deterioration affecting one in 3500 to 5000 newborn boys each year. DMD is a prominent and progressive weakness in limb muscles and postural muscles leading to spinal scoliosis and decreased exercise capacity.

It also leads to joint contractures, reduced muscle bulk, and bone fragility/osteoporosis. Along with these shortfalls, there is a decline in respiratory function because of diaphragm wasting leading to the patient being either placed on nighttime assistive ventilation or tracheostomy and ventilator. They are usually confined to a wheelchair by their early teens and typically succumb in their middle to late twenties from cardiomyopathy. And while great strides have been made to improve the orthopedic situation and respiratory status, cardiomyopathy remains the primary contributor to DMD mortality. There is no cure for this disorder or are there effective treatments clinically demonstrated to halt, prevent or reverse DMD muscle deterioration.

There are several ongoing experimental therapeutics featuring gene and cell-based strategies. One is exon-skipping. It has shown great promise but unfortunately, only a small subset of Duchenne patients benefit from this targeted approach. In clinical application, synthetic muscle membrane stabilizers for treating Duchenne patients have several attractive features. Primarily is the way copolymers as cell membranes interfacing molecules could in principle treat all of these patients regardless of their genetic lesion. On the other hand, the biggest limitation right now is this is not a cure so would require chronic treatment for these patients (Houang et al, 2018).

Research showing promise

Interactions between nutrition, metabolism and skeletal muscles have long been known as the muscle is the major metabolic organ. It consumes more calories than any other so there is a need to discuss these interactions and provide some direction for future research. There are many excellent reviews regarding the many genes which when mutated cause muscular dystrophy. Duchenne is the most common form and is very severe in patients. It is usually identified between three and five years old when the patient has difficulty learning to walk or get off the floor.

Steroid therapy is begun around age six and they usually get their first wheelchair by the age of twelve. Between five and ten years old the children start prophylactic treatment for heart failure and by age nineteen they require nighttime assisted ventilation. Most of those who are afflicted die between twenty and forty from cardiac or pulmonary deficiencies.

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While supportive care has increased the length of life for Duchenne patients, effective treatment still eludes the research community. One glaring problem noted with DMD is weight gain. Part of this can be attributed to steroid use. The other can be attributed to inactivity. As they age, unless a gastric tube is inserted, they can actually lose weight due to difficulty swallowing and constipation. This study has reported that in some cases, increasing the percentage of slow fibers, muscle fibers resistant to the effects of MD, can be seen to have some benefits. Supplements have also been explored to be combined with other treatments to either cause an additional benefit or make it possible for doctors to decrease the dose of co-therapy pharmaceuticals. This is great news as this could lead to a decrease in side-effects with a decrease in dosage (Heydemann, 2018).

The next step in the research

Nanobiotechnology-based therapies hold great promise to replace and repair the mutated dystrophin gene in the hopes of changing the disease course. There have been two items, one approved in Europe and the other in the US, to offer critical insight in how to move DMD Nanotherapy to human patients.

Progress in novel optimized nano-delivery may further improve emerging molecular therapeutic modalities for this disease. The small size and modular flexibility of the nanotechnology provides an excellent platform for the development of drug and gene therapies that target the etiology of DMD. In the last decade, improvements in analytical chemistry, instrumentation, structural biology protein, and nucleic acid engineering and availability of nanomaterials have fostered an explosion in nanotechnology for DMD. Approval of the read-through drug Ataluren and exon-skipping drug Exondys51 have set good examples on the path forward for this disease.

Preclinical studies in small and large animals as well as early phase human trials have been instrumental in the development of Nanotherapy for DMD. It is clear from these studies that some strategies will not be appropriate for MD therapy. However, some of the emerging need technologies are likely going to change the landscape of DMD Nanotherapy in the next few years. With the extensive possibilities of nanotechnology, the future of etiology-based treatment should be exciting in the coming years. Research needs to continue the fight for a treatment and cure (Nance et al, 2018).

Duchenne muscular dystrophy is a lethal disorder caused by a mutation of the dystrophin gene. In 2016, the FDA approved eteplirsen for treatment to skip DMDexon51 applicable to only 13% of DMD patients. In order to reach the other 87% a cocktail of antisense oligonucleotides are needed to target the exons that need to be skipped to potentially stop this disease in its tracks. Muscular dystrophy is a group of more than 30 different inherited disorders that are characterized by progressive weakness and degeneration of muscle fibers. The most common form is Duchenne that has 79 exons in each dystrophin gene that is mutated. It is the longest gene in humans and it is felt the long size of this gene is why it is a hotspot for mutations as compared to other genes. It is approximated that 80% to 97% of DMD patients can be helped by this multiple-exon skipping (Alslesh et al, 2018).

Prednisone is the current drug of choice in treating children with Duchenne to decrease chronic inflammation. This medicine also has drastic side effects like weight gain, steroid-induced diabetes and decreased immunity. A medicine traditionally used to treat cardiomyopathy in adults is now being researched for use in children with DMD as cardiomyopathy is the leading cause of death in these individuals. As a change from steroids, there is a medicine under development that combines the beneficial effects of these medicines while showing an improved safety component in experimental models. The findings of this study show promise for both current and future patients (Heier et al, 2019).

Work cited Duchene
Aslesh, T. et al. (2018). Skipping multiple exons to treat Duchenne Muscular Dystrophy-Promises and challenges. Biomedicines, 6(1).

Heier, C. et al. (2019). New research insights hold promise for kids with Duchenne muscular dystrophy. Children’s National Health System.

Heydemann, A. (2018). Skeletal muscle metabolic in Duchenne and Becker Muscular Dystrophy Implication for Therapy. Dietary Intake and Musculoskeletal Health. Nutrients, 10(6).

Houang, E. et al. (2018). Muscle membrane integrity in Duchenne muscular dystrophy: Recent advances in copolymer-based muscle membrane stabilizers. Skeletal Muscle.

McDonald,C.M. & Mercuri, E. (2018). Evidence-based are in Duchenne Muscular Dystrophy. The Lancet Neurology-London, 17(5).

Muscular Dystrophy Association. (2011). Facts about Duchenne and Becker Muscular Dystrophy. Muscular Dystrophy Association, Inc. Fighting Muscle Disease.

Nance, M.E. et al. (2018). Nanotherapy for Duchenne muscular dystrophy. WIREs Nanomedicine and Nanobiotechnology, 10(2).

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Comments

Duchenne Muscular Dystrophy 'runs' in my family. My father lost two older brothers to it and one of his sisters lost two sons to it. The younger cousin was the same age as my younger brother so I remember him well. He died when he was 20 years old. Because of this family connection, I have tried to stay up to date on MDA's progress.