Strategies for muscle-specific targeting of adenoviral gene transfer vectors.

摘要

Currently, adenoviral transfer of therapeutic genes such as dystrophin is hampered by low transduction efficiency of adult skeletal muscle. This is largely due to the lack of appropriate virus attachment receptors on the myofiber surface. Recent studies in transgenic mice revealed that upregulation of Coxsackie- and adenovirus receptor improves gene transfer efficiency by approximately ten-fold. Conversely, the vector load that needed to be administered to achieve sufficient gene transfer could be lowered significantly. Reduced viral vector loads may help to control virally mediated toxicity and immunogenicity. To date, there are no drugs or methods known to increase Coxsackie- and adenovirus receptor expression in skeletal muscle that would be easily applicable in humans. However, alternative strategies such as vector retargeting are currently being investigated that may allow for an increase in binding of adenoviral vectors to skeletal muscle. Recent experiments have shown that directed mutagenesis of the adenoviral fiber knob allows for a significant reduction in Coxsackie- and adenovirus receptor binding and for introduction of a new binding domain. Therefore, vector retargeting towards efficient and specific infection of skeletal muscle may be achieved by directed genetic alteration of adenoviral capsid proteins.