Emerging Strategies in the Treatment of Duchenne Muscular Dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is a progressive X-linked degenerative muscle disease due to mutations in the DMD gene. Genetic confirmation has become standard in recent years. Improvements in the standard of care for DMD have led to improved survival. Novel treatments for DMD have focused on reducing the dystrophic mechanism of the muscle disease, modulating utrophin protein expression, and restoring dystrophin protein expression. Among the strategies to reduce the dystrophic mechanisms are 1) inhibiting inflammation, 2) promoting muscle growth and regeneration, 3) reducing fibrosis, and 4) facilitating mitochondrial function. The agents under investigation include a novel steroid, myostatin inhibitors, idebenone, an anti-CTGF antibody, a histone deacetylase inhibitor, and cardiosphere-derived cells. For utrophin modulation, AAV-mediated gene therapy with GALGT2 is currently being investigated to upregulate utrophin expression. Finally, the strategies for dystrophin protein restoration include 1) nonsense readthrough, 2) synthetic antisense oligonucleotides for exon skipping, and 3) AAV-mediated micro/minidystrophin gene delivery. With newer agents, we are witnessing the use of more advanced biotechnological methods. Although these potential breakthroughs provide significant promise, they may also raise new questions regarding treatment effect and safety.

Advancements in magnetic resonance imaging‐based biomarkers for muscular dystrophy

“…Perhaps the most compelling reason for the growth in MRI research in hereditary myopathies is the requirement for new biomarkers that can be used in therapeutic trials for these diseases. The past decade has seen a significant rise in the number of interventional trials in muscular dystrophy . In developing and completing these trials, many investigators have come to recognize the advantages to having more sensitive and objective biomarkers to monitor treatment effects …”

“…The past decade has seen a significant rise in the number of interventional trials in muscular dystrophy. 15 In developing and completing these trials, many investigators have come to recognize the advantages to having more sensitive and objective biomarkers to monitor treatment effects. 16,17 The primary advantage that MRI offers to researchers in muscular dystrophy is the ability to detect very small increments of true pathologic change in skeletal muscle.…”

Therapies that are available and under development for Duchenne muscular dystrophy: What about lung function?

“…Appropriate expectoration of secretions is also crucial for airway clearance, decreasing the risk of infections and atelectasis and preserving the lung parenchyma available for gas exchange. Improvement in cough efficacy should, therefore, be an additional goal for future research . However, apart from pulmonary morbidity, early heart failure also increases the burden of Duchenne muscular dystrophy and it would be of great clinical significance that future studies combine both respiratory and cardiovascular outcomes …”

“…In parallel, outcomes strongly correlated with quality of life need to be widely used to render the findings of the studies clinically therefore, be an additional goal for future research. 71,72 However, apart from pulmonary morbidity, early heart failure also increases the burden of Duchenne muscular dystrophy and it would be of great clinical significance that future studies combine both respiratory and cardiovascular outcomes. 73 Another point to highlight is that in clinical practice gaps often occur during the transition of pediatric patients to adult health care services and therefore it would be very helpful that this fact be considered when designing longitudinal cohort studies.…”

Myopathy: Recent Progress, Current Therapies, and Future Directions

“…Shieh leads off this issue by reviewing strategies to treat Duchenne muscular dystrophy [2]. In addition to the two FDA-approved treatments for this disease, corticosteroids and the exon-skipping agent eteplirsen, consideration is given to other agents currently under investigation that may improve or slow the progression of weakness by reducing inflammation, promoting muscle regeneration, reducing fibrosis, facilitating mitochondrial function, or restoring functional dystrophin protein expression.…”