Novel Delivery of Molecular Therapeutics to the Heart Using Non-biologic Constructs (PPMO/Morpholino) in Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is an X-linked recessive disease caused by the absence of the cytoskeletal protein dystrophin. There is no effective treatment and affected individuals die from respiratory failure and cardiomyopathy by age 30. One recent approach to treating DMD is antisense-mediated exon skipping to restore dystrophin protein. Most mutations causing DMD disrupt the open reading frame, leading to aberrant translation and the lack of dystrophin protein. The related allelic disorder Becker muscular dystrophy (BMD) is caused by mutations that create shortened, but in-frame transcripts, producing a partially functional dystrophin, leading to a milder phenotype. Antisense-induced exon-skipping strategies aim to remove the mutated or additional exon(s) to restore the reading frame and, consequently, induce the expression of these “BMD-like” shortened forms of the dystrophin protein, retaining crucial functions. Various types of antisense oligonucleotides (AOs) exist and have been shown to cause exon skipping in vivo and improve skeletal muscle function in animal models and, in two independent phase I clinical trials, to cause exon skipping in humans. More recently, phosphorodiamidate morpholino oligomers (PMOs) have been directly conjugated to cell-penetrating peptides (CPPs), to form PPMOs, thereby improving their efficacy and allowing for a more systemic delivery. This conjugation allows PPMOs to reach the heart, restoring full cardiac function in animal models, at non-toxic doses. These PPMOs show great potential for improving function of both skeletal and cardiac muscle in DMD patients, though a number of hurdles remain to be overcome.