Systemic delivery of AAV8 in utero results in gene expression in diaphragm and limb muscle: treatment implications for muscle disorders.

One of the major challenges in the treatment of primary muscle disorders, which often affect many muscle groups, is achieving efficient, widespread transgene expression in muscle. In utero gene transfer can potentially address this problem by accomplishing the gene delivery when the tissue mass is small and the immune system is immature. Earlier studies with systemic in utero adeno-associated viral (AAV) vector serotype 1 gene delivery to embryonic day 16 (E-16) pups resulted in high levels of transduction in diaphragm and intercostal muscles, but no detectable transgene expression in limb muscles. Recently, newer AAV serotypes, such as AAV8, have shown widespread and high transgene expression in skeletal muscles and diaphragm by systemic delivery in adult and neonatal mice. We tested AAV8 vector gene delivery by intraperitoneal administration in E-16 mice in utero. Using an AAV8 vector carrying a lacZ reporter gene, we observed high-level transduction of diaphragm and intercostal muscles and more moderate transduction of multiple limb muscles and heart. Our current studies show the potential of AAV8 to achieve widespread muscle transduction in utero and suggest its therapeutic potential for primary muscle disorders.