Off-Target Effects and Safety Aspects of Phosphorothioate Oligonucleotides

Abstract

In addition to the intended sequence-specific downregulation of the gene target, antisense and siRNA oligonucleotides can trigger off-target effects that are often caused by a particular chemical modification. The phosphorothioate backbone modification is dominating the clinical development of antisense agents, but reports about unspecific effects with clinical relevance, such as influence on blood clotting, activation of the complement system, and increasing levels of transaminases, shed doubt on its therapeutic value. In vitro mechanistic experiments have shown a class-related interaction of phosphorothioates with cellular pathways involved in apoptosis regulation, endoplasmatic reticulum stress, and glycolysis. Although clinical safety data indicate that severe adverse effects of phosphorothioates are not dose limiting, concerns of unspecific effects, in particular hepatotoxicity, after long-term treatment remain.