The Development of an Ultrasound-mediated Nucleic Acid Delivery System for Treating Muscular Dystrophies

Abstract

Muscular dystrophies are a group of heterogeneous diseases that are characterized by progressive muscle weakness, wasting and degeneration. These muscular deficiencies are often caused by the loss of the protein dystrophin, a crucial element of the dystrophin-glycoprotein complex of muscle fibers. Duchenne muscular dystrophy (DMD) is a fatal, X-linked muscular disease that occurs in 1 out of every 3500 males. Therefore, feasible strategies for replacing or repairing the defective gene are required; however, to date, no effective therapeutic strategies for muscular dystrophies have been established. In this review, we first introduce gene therapies mediated by adeno-associated viruses (AAVs) including a functional dystrophin cDNA or antisense oligonucleotide (AO)-induced exon-skipping therapies, which are designed to exclude the mutated or additional exon(s) in the defective gene and thereby correct the translational reading frame. Recently, we developed "Bubble liposomes" (BLs), which are polyethylene glycol (PEG)-modified liposomes entrapping echo-contrast gas that is known as ultrasound (US) imaging gas. BL application combined with US exposure can function as a novel gene delivery tool, and we demonstrate that the US-mediated eruption of BLs is a feasible and efficient technique to deliver plasmid DNA or AOs for the treatment of muscular dystrophies.