Exon Skipping and Dystrophin Induction in Cardiac Muscle

The requirement of muscle damage for effective delivery and AON induced dystro-phin expression is further supported by the result obtained in the cardiac muscle in the mdx mice after systemic treatment of both 2OMePS AON and PMO. Cardiac muscles in mdx mice are less affected by the dystrophic process and no significant pathology and functional impairment can be obviously demonstrated until late age. Consistently, only minimum amount of dystrophin expression can be detected in the cardiac muscle even after repeated injections of both 2OMePS AON and PMO in all mdx mice aged 6 months or younger (Lu et al. 2005; Alter et al. 2006), whereas the same treatment can induce high levels of dystrophin in skeletal muscles. There is a possibility that the special tissue structure (vasculature and membrane) and pattern of metabolism or gene expression regulation could be responsible for lower efficiency of AON delivery or exon skipping inside myonuclei. However, direct injection of AON into cardiac muscles showed effective dystrophin induction, suggesting that lower delivery efficiency is perhaps the most critical factor (Vitiello et al. 2008). This is further supported by the restoration of dystrophin in cardiac muscles via AAV-mediated AON delivery (Denti et al. 2008).

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