Systemic Delivery of the Interleukin-1 Receptor Antagonist Protein Using a New Strategy of Direct Adenoviral-Mediated Gene Transfer to Skeletal Muscle Capillary Endothelium in the Isolated Rat Hindlimb

Abstract

Overview summary Here we report highly efficient adenoviral-mediated gene transfer to the rat skeletal muscle capillary endothelium and muscle fibers during vascular isolation of the hindlimb. Gene transfer over a 109–1012 particle/ml range to the gastrocnemius capillary endothelium and muscle fibers is highly efficient and titer dependent, reaching maximum transduction rates in these tissue of 71 ± 7% and 25 ± 5%, respectively, 5 days after gene transfer. Adenovirus-induced inflammation in the skeletal muscle was not observed and distant organ gene transfer was minimal or absent. When adenoviral interleukin-1 receptor antagonist (Ad-IL-1ra) was used to transduce the gastrocnemius capillary endothelium and muscle fibers, serum IL-1ra levels were 185 ± 20 pg/ml. Athymic rats given Ad-IL-1ra had serum levels of 493 ± 62 pg/ml IL-1ra 14 days after transduction and IL-1ra was detected for up to 98 days. This gene transfer strategy results in substantial transduction of capillary endothelium as well as skeletal muscle fibers sufficient to achieve pharmacologic levels of recombinant protein without evidence of local tissue injury.