In Vivo Administration of Splice Switching PNAs Using the mdx Mouse as a Model System

Abstract

Duchenne muscular dystrophy (DMD) is the most common and severe form of muscular dystrophy and is caused by gene mutations that abolish production of functional dystrophin muscle protein. A promising new treatment exploits specifically targeted RNA-acting drugs that are able to partially restore the dystrophin protein. The mdx mouse model (animal model of DMD) serves as a good in vivo model for testing these antisense drugs. The simplest in vivo test, which circumvents the systemic circulation, is intramuscular administration of the compound. After 7 days it is possible to detect exon skipping by reverse transcriptase PCR, and newly synthesized dystrophin-positive fibers by immunohistochemistry and western blotting. All muscles, including the heart, are affected by the disease and must be treated. Therefore the use of antisense therapy for treatment of DMD requires systemic administration, and the model is also useful for systemic administration.