Cardiac therapies for Duchenne muscular dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is a devastating disease that results in life-limiting complications such as loss of skeletal muscle function as well as respiratory and cardiac complications. Advanced therapeutics in pulmonary care have significantly reduced respiratory complication-related mortality, making cardiomyopathy the main determinant factor of survival. While there are multiple therapies such as the use of anti-inflammatory drugs, physical therapy, and ventilatory assistance targeted toward delaying the disease progression in DMD, a cure remains elusive. In the last decade, several therapeutic approaches have been developed to improve patient survival. These include small molecule-based therapy, micro-dystrophin gene delivery, CRISPR-mediated gene editing, nonsense readthrough, exon skipping, and cardiosphere-derived cell therapy. Associated with the specific benefits of each of these approaches are their individual risks and limitations. The variability in the genetic aberrations leading to DMD also limits the widespread use of these therapies. While numerous approaches have been explored to treat DMD pathophysiology, only a handful have successfully advanced through the preclinical stages. In this review, we summarize the currently approved as well as the most promising therapeutics undergoing clinical trials aimed toward treating DMD with a focus on its cardiac manifestations.

Keywords: ACE inhibitor; CRISPR; DMD; Duchenne muscular dystrophy; cardiac; cardiomyopathy; exon skipping; gene editing; gene therapy.

Figure 1.

Schematic diagram of exon skipping. (a) Regular splicing. (b) Antisense oligonucleotide–mediated exon skipping. Antisense oligonucleotide binds to and restricts the splice acceptor site causing the spliceosomes and the donor site to move onto the next splice acceptor site. As a result, exon B gets skipped and a shortened mRNA is produced.

Figure 2.

Challenges with antisense oligonucleotide delivery. Figure adapted from Godfrey et al.