Antisense oligonucleotide delivery to cardiac muscle: Knocking on a locked door

Cardiac involvement in Duchenne Muscular Dystrophy (DMD) is evident in nearly a third of all patients, with up to 40% succumbing to heart disease. Whereas DMD is caused by a lack of functional dystrophin, Becker Muscular Dystrophy (BMD) is characterized by expression of an internally truncated, functional dystrophin protein. Nearly 90% of BMD patients over the age of 40 have evidence of cardiac involvement in the disease process. The most widely used animal model, the mdx mouse, has similar skeletal pathology to DMD patients, however, the cardiac pathology is more representative of BMD patients (i.e. late onset of cardiac involvement). Advances in gene therapy have demonstrated both in vivo and in vitro delivery of constructs to skeletal muscles leading to expression of a functional dystrophin protein. Cardiac delivery of gene medicines has proved more difficult and unrewarding. We have been able to demonstrate antisense-induced exon skipping in cardiac cell cultures derived young mdx mice. Multi-exonic skipping and novel delivery methods have improved in vitro results, however in vivo experiments still lack definitive success. Besides the morphologic and functional differences between skeletal and cardiac muscle, a potential reason for the lack of success maybe the absence of pathology in the younger animals, leading to decreased uptake of gene therapy in vivo. We are pursuing several lines of research to further enhance levels of exon skipping in cardiac cells in vitro and in vivo