INTRODUCTION Therapeutic gene silencing is a huge promise for the treatment of a variety of diseases. The translation of this widely used scientific technique toward clinical application has been hindered by insufficient ADME properties of antisense and siRNA oligonucleotides. Despite reasonable therapeutic response after local administration, reaching adequate concentrations at the site of action after systemic application is still a major hurdle and this has resulted in poor efficiency in preclinical and clinical situations. AREAS COVERED This review focuses on the influence on the ADME parameters of chemical modifications already tested in clinical trials, such as phosphorothioates (PSs), 2'-modified agents, including locked nucleic acids (LNA) and phosphorodiamidate morpholino oligomers (PMO). The dominating PS backbone modification, while conferring adequate nuclease resistance and improving biodistribution, has been shown to be involved in unspecific protein binding and off-target effects on apoptosis pathways. PS-free antisense agents such as PMO generally show poorer pharmacokinetic characteristics. EXPERT OPINION In terms of pharmacokinetics and cell membrane permeation, there is currently no efficient alternative to PS, although doubts about long-term toxicity of this class still remain. Consequently, improved structural modifications or galenic formulations are deemed necessary to create entities with higher efficiency and lower toxicity.
Influence of diverse chemical modifications on the ADME characteristics and toxicology of antisense oligonucleotides.