Antisense oligonucleotides for the treatment of cardiomyopathy in Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is an X-linked recessive fatal neuromuscular disorder characterized by progressive muscle degeneration which affects one in 3500-5000 males born worldwide. DMD is caused by loss-of-function mutations in the dystrophin (DMD) gene encoding for dystrophin, a cytoskeletal protein that supports the structural integrity of myofibers during cycles of muscle contraction and relaxation. DMD patients do not only experience skeletal muscle deterioration but also severe cardiomyopathy, which is recognized as the current leading cause of death for the disease. Among the therapies being developed, exon skipping using antisense oligonucleotides (AOs) is one of the most promising approaches. AOs effectively restore dystrophin expression in skeletal muscles; however, they are highly inefficient in the heart due to endosomal entrapment. Improving skeletal muscle function without restoring dystrophin expression in cardiac tissue may exacerbate cardiomyopathy due to increased voluntary activity. This review consolidates the preclinical antisense approaches to improve dystrophin restoration, with a special focus on the heart.