Albumin-Binding Fatty Acid–Modified Gapmer Antisense Oligonucleotides for Modulation of Pharmacokinetics

Abstract

Prolonged circulation and modulation of the pharmacokinetic profile are important to improve the clinical potential of antisense oligonucleotides (ASOs). Gapmer ASOs demonstrate excellent nuclease stability and robust gene silencing activity without the requirement of transfection agents. A major challenge for in vivo applications, however, is the short blood circulatory half-life. This work describes utilisationutilization of the long circulation of serum albumin to increase the blood residence time of gapmer ASO. The method introduces fatty acid modifications into the gapmer ASOs design to exploit the binding and transport property of serum albumin for endogenous ligands. The level of albumin-/gapmer ASOs interaction, blood circulatory half-life and biodistribution was dependent on number, position, and fatty acid type (palmitic or myristic acid) within the gapmer ASO sequence and either phosphorothioate or phosphodiester backbone modifications. This work offers a strategy to optimiseoptimize gapmer ASO pharmacokinetics by a proposed endogenous assembly process with serum albumin that can be tuned by gapmer ASO design modifications.

An Albumin-Binding Domain Peptide Confers Enhanced Immunoprotection Against Viral Myocarditis by CVB3 VP1 Vaccine

“…Later, “albumin hitchhiking” effect was used by more small molecule compounds and peptide drugs to achieve dLNs enrichment ( 16 ). Meanwhile, coupling with long half-life albumins would also obviously increase the in vivo retention periods of oligonucleotides ( 17 ), compounds ( 18 ) or proteins ( 19 ).…”