When it comes to rare diseases that carry a poor prognosis, such as Duchenne muscular dystrophy (DMD), medical researchers are eager to find the “primary cure” that will rid a patient of this disease completely. This is also the approach that the general public often would like to see researchers take, and sometimes it is the approach we promise to pursue during fundraising events. 

The reality, however, is that there is far from a silver bullet cure for DMD at present. Nor is it on the immediate horizon. This is a tough pill to swallow, but for the foreseeable future, DMD disease progression will likely remain as it is (with minor improvements), with death being the end result. 

So if there is no primary cure for a disease, should medical researchers continue to pursue one aggressively? Or should researchers start thinking of how a combination of existing drugs can be utilized for their synergistic effects? 


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Angelini et al wrote a paper that argued the importance of secondary therapies in treating DMD. They wrote, “DMD is currently being addressed intensely by different research groups who aim to develop primary therapies to correct the genetic defects of the disease. However, most of the clinical trials based on both genetic or cellular approaches are still far from being of therapeutic value and have to rely on good muscle grade.” 

And the clock is ticking. Treating DMD can be likened to a race against time, and any mistake made can be costly. Angelini et al wrote, “There is no approach available that can rescue muscle damage when the muscle tissue has been completely lost and substituted by fibrotic deposits.” In other words, the musculature of DMD patients is at risk of permanent damage if attempts to preserve it fail.

Addressing Muscle Function and Inflammation 

It is laudable that DMD research is increasingly heading towards genetic territory, but until a genuine breakthrough occurs, physicians must focus their attention on 2 things: improving the quality of life of their patients and prolonging survival. 

We will look at some of the specific areas of DMD as outlined by Angelini et al and examine how they can be improved. 

First, altered regenerative capacity. “Dystrophin muscles suffer from time-dependent exhaustion of tissue regenerative capacity, but the underlying mechanisms are still under investigation and debated,” the researchers wrote. “A line of evidence suggests that, despite their increased number, dystrophic stem cells have limited regenerative potential due to a dysregulated microenvironment that causes their poor or improper activation, not sufficient to regenerate the tissue.” 

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Previous studies have attempted to rescue muscle function by inhibiting myostatin, which is a strong inhibitor of myoblasts differentiation. However, this approach has proved unsuccessful, causing researchers to test out histone deacetylase (HDAC) inhibition instead. A study involving givinostat, an HDAC inhibitor, successfully increased muscle regeneration and reduced tissue necrosis and fibrosis, thus improving the quality of muscular tissue. This is good news: it means that muscles can be kept healthier while awaiting future therapies. 

The second area examined was chronic inflammation. The initial therapeutic approach to this issue was to prescribe glucocorticoids. However, long-term glucocorticoid use can cause adverse effects, such as weaker bones, high blood pressure, and weight gain. Medical researchers then turned to the steroid analog vamorolone, which has demonstrated membrane-stabilizing and anti-inflammatory properties, with fewer adverse effects. Another combination of drugs, spironolactone and lisinopril, has been shown to ameliorate inflammation and fibrosis in the heart and skeletal muscles of dystrophic mice.

Considering the Psychosocial Impact

The third issue that bears discussion is the psychosocial impact of DMD, a point raised by Iftikhar et al in their study on current and emerging therapies for DMD. This point, although it does not relate to the musculature directly, is of vital importance. 

Iftikhar and colleagues explained why: “Patients with DMD have a higher rate of intellectual disability including learning disorders, autism spectrum disorders, and attention deficit hyperactivity disorder (ADHD). Increased risks of anxiety and depression have been observed in DMD patients.” 

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This means that the primary physician should be on the lookout for signs of any of these conditions, which would warrant further therapeutic intervention. Anxiety and depression can often be managed with typically prescribed antidepressants, such as fluoxetine and sertraline. Behavioral issues, such as emotional dysregulation and aggression, can be managed with alpha-adrenergic agonists and atypical antipsychotics. 

Importantly, caregivers need to be given all the tools they need to support the DMD patients under their care. Iftikhar et al wrote, “Planning and education for adult caregivers are suggested to aid in patient care to provide the optimal psychological support.”

This means that physicians need to ensure that the psychological status of both patient and caregiver is supported. “Routine assessments of mental health of the patient and family at every visit is suggested coupled with recommendations for standard cognitive behavioral therapy or pharmacological intervention if deemed necessary,” Iftikhar and colleagues wrote. 

Evolving Treatment Strategies

The complex issues highlighted in this article demonstrate that there is no one-size-fits-all approach to DMD patient care. Indeed, physicians need to always be ready to pick up on new issues that come to their attention during each follow-up. 

And what else can be said about medical research into DMD therapies? Angelini and colleagues concluded, “The most promising and relevant studies would lead to a more preserved musculature [and] a better patient life expectancy thus improving eligibility for studies or clinical trials aiming to correct the genetic defect at the basis of the DMDs.” 

References

Angelini G, Mura G, Messina G. Therapeutic approaches to preserve the musculature in Duchenne Muscular Dystrophy: The importance of the secondary therapies. Exp Cell Res. Published online December 7, 2021. doi:10.1016/j.yexcr.2021.112968

Iftikhar M, Frey J, Shohan MJ, Malek S, Mousa SA. Current and emerging therapies for Duchenne muscular dystrophy and spinal muscular atrophyPharmacol Ther. 2021;220:107719. doi:10.1016/j.pharmthera.2020.107719