Systemic Delivery of Therapeutic Genes in DMD Models

To date efficient widespread expression in skeletal and cardiac muscles has not been demonstrated in large animal models of DMD. Intravascular delivery of AAV vectors demonstrated the proof of concept in mdx mice by restoring functional correction of skeletal muscle, diaphragm and heart disease (Bostick et al. 2009; Gregorevic et al. 2006; Wang et al. 2005). In normal neonate dogs, injection of AAV-9 resulted in expression of a reporter gene, in a dose-dependent manner, in widespread skeletal muscle but not in the heart (Yue et al. 2008). In another study, AAV-6 was the most efficient vector serotype in cardiac gene transfer following percutaneous transendo-cardial delivery to normal adult dogs (Bish et al. 2008). In both studies, no cellular immune responses were observed. More studies are required to determine whether these results could address safety scale-up issues in DMD dogs using a relevant therapeutic transgene, and whether the potential risk of immune responses to the vector and/or transgene may be detrimental to the diseased heart.

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