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.

Keywords: Duchenne muscular dystrophy; Dystrophin; Gene therapy.

Fig. 1

The canonical dystrophin protein, Dp427, and the different isoforms: Dp260, Dp140, Dp116, and Dp71. The numbers under the constructs show the map to the approximate exon encoding that region. N-term = N terminal domain, R# = spectrin repeat number, H# = hinge number, CR = cysteine-rich domain, C-term = C terminal domain

Fig. 2

The 3 AAV micro/minidystrophin agents currently under investigation. A Sarepta/Nationwide’s agent uses an AAVrh74 capsid, with MHCK7 promoter [84]. B SGT-001 uses an AAV9 capsid, with CK8 promoter [86]. C PF-06939926 uses an AAV9 capsid, with a muscle-specific promoter that has not been publicly disclosed at the time of this review [88]. N-term = N terminal domain, R# = spectrin repeat number, H# = hinge number, CR = cysteine-rich domain