A Novel Approach for Gene Medicine: Synthetic Poly-L-lysine/serine Copolymer Enhances Bioactivity of Antisense Oligonucleotides

Abstract

Antisense oligonucleotides have therapeutic potential as inhibitor of gene expression. Water soluble and nuclease resistant-polymers complexed with the antisense oligodeoxynucleotide which specifically inhibits the production of interleukin-1 β were prepared using poly-L-lysine/ L-serine and its polyethylene glycol 5000 conjugate and evaluated their activity in vitro and in vivo. These complexes biologically inhibited interleukin-1 β production in a dose-dependent and sequence-specific manner at nanomolar levels in lipopolysaccride-stimulated human macrophage-like, U937 cells. Moreover, in vivo studies using mouse endotoxin shock model, it had a strong efficacy in a dose-dependent and sequence-specific manner. The mice(n=10), administered with the antisense complex at 100mg/kg, survived for more than 7days. These carriers may give a promise for developing nucleic acid drug in clinical use.