Duchenne muscular dystrophy (DMD) is a rare X-linked disease that results in progressive muscular weakness across the body, encompassing the skeletal and cardiac muscles and the diaphragm.
Like hemophilia, another X-linked disorder, DMD was almost universally fatal before the introduction of therapies capable of extending survival. Unlike hemophilia, DMD is not as easily noticeable to the naked eye. Perhaps the single most telling sign of DMD in a young patient is Gower’s maneuver, which is characterized by an individual using his arms to walk up his body when attempting to stand upright.
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Before the age of proper diagnostics and the widespread availability of imaging studies, parents could only have adopted a “watch and wait” approach; anxiously, they would watch and wait, wait and watch, and over the years, come to see their son slowly lose his ability to ambulate as his muscular function declines. The doctor would not be able to do much beyond offer a few words of comfort; before the advent of genetic studies, it was simply impossible to understand the hereditary nature of the disease, let alone any attempts to cure it.
The harsh reality is that most patients, by their 3rd or 4th decade of life, would die from either cardiac complications or respiratory illnesses. Before then, a patient would likely need a caregiver to attend to his needs and to aid him in performing activities of daily living. Due to the depressing effect of the disease on an individual’s social life, loneliness is a common problem.
Even before the arrival of modern therapeutics, palliative care for patients with DMD was taking shape, and home caregivers familiar with dystrophinopathies would ensure that the patient gets the care he needs, both at a physical and a psychosocial level.
“The development of palliative therapies through the years have extended the average lifespan of patients, from approximately 20 years before these palliative therapies to about 40 years with the therapies,” Heydemann and Siemionow wrote in Biomedicines.
DMD Care Today
DMD care today is dominated by the use of corticosteroids due to their immunomodulatory properties.
“Glucocorticoids bind to and activate the [glucocorticoid receptors], regulating several physiological processes including immune response, metabolism, mood, and cognitive function,” Kourakis and colleagues wrote in the Orphanet Journal of Rare Diseases.
Prednisolone and deflazacort are 2 glucocorticoids that are among the most frequently prescribed drugs in DMD. Prednisolone, 1 of the most important drugs in medicine today, is also used to treat rheumatic, dermatological, and ophthalmological diseases, among others. Prednisolone is used in DMD to slow disease progression and delay disease milestones.
Deflazacort is comparable to prednisolone in terms of its effects in delaying loss of ambulation in patients with DMD. It has also been associated with other positive outcomes, such as the preservation of cardiac, pulmonary, and motor function. However, its precise effects on bone health is still subject to debate.
Studies suggest glucocorticoids can prolong ambulation by 2 to 3 years and slow pulmonary deterioration. However, the use of glucocorticoids remains controversial due to the adverse effects frequently associated with prolonged use; these may include weight gain, stunted growth, a cushingoid appearance, and decreased bone mineral density, among others.
This often puts both patients and their caregivers in a bind—do patients continue with their course of glucocorticoid drugs, or does an eventual depression in their quality of life make matters worse overall? Would some patients prefer to be off steroid therapy but with the dreaded certainty that disease progression will continue unhindered? How do finite human beings weigh up such issues that are both delicate and intractably heavy in equal measure?
“These adverse effects, in combination with the already progressive, terminal nature of DMD, may further place undue strain on patients and their families, and in particular, increase parental stress,” Kourakis and colleagues wrote. “For this reason, short-term intermittent prednisone treatment has been investigated as an alternative to chronic therapy.”
Novel Solutions Ahead
Novel, experimental therapies aim to either provide longer lasting protection against disease progression or cure the disorder entirely.
“Despite the many years of corticosteroids being the sole pharmaceutical prescribed for DMD patients, many promising therapies are on the horizon for these patients,” Heydemann and Siemionow wrote.
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Among the highly prized solutions on the table is gene correction, or the introduction of the missing dystrophin gene into the body. Theoretically, this should cure the disease since the missing dystrophin gene drives pathophysiology.
The challenge with gene therapy is that the missing gene appears to be too large for the delivery method of choice: adeno-associated viruses. Scientists are studying ways to shrink the dystrophin gene while retaining most of the functions of the full-length protein. In addition, scientists have to deal with the immune system fighting against any foreign bodies introduced into the body.
Another potential therapy is the manipulation of muscular metabolism for the benefit of patients with DMD. The goal here is to upregulate phosphorylated AMP-activated protein kinase (pAMPK). A proposed strategy is to use metformin to make the cell believe that it is low on ATP; this will increase mitochondrial production and metabolism. This increase in metabolic activity will likely benefit muscle cells. An advantage of this strategy is that metformin is already well-known and well-tested as a diabetic drug; hence, it is likely to be well-tolerated when used in a patient with DMD.
What should we make about the ongoing development of these novel therapies? Heydemann and Siemionow offer both perspective and hope. They wrote, “The most important point is that many different strategies are being investigated. This will make success of at least 1 of the pharmaceuticals more likely with these many avenues and momentum, it is not surprising that many clinical trials to combat DMD are occurring.”
References
Kourakis S, Timpani CA, Campelj DG, et al. Standard of care versus new-wave corticosteroids in the treatment of Duchenne muscular dystrophy: Can we do better?. Orphanet J Rare Dis. Published online March 4, 2021. doi:10.1186/s13023-021-01758-9
Heydemann A, Siemionow M. A brief review of Duchenne muscular dystrophy treatment options, with an emphasis on two novel strategies. Biomedicines. Published online March 9, 2023. doi:10.3390/biomedicines11030830
