Key result
Following systemic AAV9 administration in neonatal mice, the α-MHC promoter provided the most cardiac-specific transgene expression, while the Desmin promoter achieved high expression across both cardiac and skeletal muscle.
The alpha-MHC promoter enables highly specific cardiac transgene expression, while the Desmin promoter allows broad expression across cardiac and skeletal muscle following systemic AAV9 delivery.
Informs preclinical AAV9 promoter selection for cardiac gene therapy; leaves open translation to larger models or humans.
The AAV9 capsid displays a high natural affinity for the heart following a single intravenous (IV) administration in both newborn and adult mice. It also results in substantial albeit relatively lower expression levels in many other tissues. To increase the overall safety of this gene delivery method we sought to identify which one of a group of promoters is able to confer the highest level of cardiac specific expression and concurrently, which is able to provide a broad biodistribution of expression across both cardiac and skeletal muscle. The in vivo behavior of five different promoters was compared: CMV, desmin (Des), alpha-myosin heavy chain (alpha-MHC), myosin light chain 2 (MLC-2) and cardiac troponin C (cTnC). Following IV administration to newborn mice, LacZ expression was measured by enzyme activity assays. Results showed that rAAV2/9-mediated gene delivery using the alpha-MHC promoter is effective for focal transgene expression in the heart and the Des promoter is highly suitable for achieving gene expression in cardiac and skeletal muscle following systemic vector administration. Importantly, these promoters provide an added layer of control over transgene activity following systemic gene delivery.
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Pacak et al. (2008) studied Gene therapy biodistribution (n=30). Tissue-specific promoters (α-MHC, Desmin) in AAV9 vectors vs. CMV, MLC-2, and cTnC promoters was evaluated on Tissue-specific β-galactosidase expression levels. Following systemic AAV9 administration in neonatal mice, the α-MHC promoter provided the most cardiac-specific transgene expression, while the Desmin promoter achieved high expression across both cardiac and skeletal muscle.
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