Respirable antisense oligonucleotides: a new, third drug class targeting respiratory disease

Abstract

To describe the potential of a new class of respiratory drugs, respirable antisense oligonucleotides. The first respirable antisense oligonucleotide, EPI-2010, has now reached clinical trials. It has shown intriguing initial indications of efficacy and the potential to be the first once-per-week asthma preventative. Respirable antisense oligonucleotides are capable of addressing targets that have proven to be intractable to traditional 'small molecule' approaches, and against which newer monoclonal antibody strategies may also not be optimal. Respirable antisense oligonucleotides functionally, but not genetically, ablate gene expression by blocking the template function of target respiratory messenger RNAs by as yet incompletely defined mechanisms. They do so with an avidity and specificity which can be several orders of magnitude greater than those shown by small molecule antagonists for their protein targets. The target properties of respiratory messenger RNAs are strikingly different from those of respiratory proteins, enabling respirable antisense oligonucleotides to offer the potential of longer duration of effect, increased specificity of effect, and lack of systemic side effects compared with either traditional small molecule protein antagonists or monoclonal antibodies. Respirable antisense oligonucleotides represent a new, third class of respiratory drugs with the potential to extend the range of therapeutic responses to otherwise intractable respiratory targets, and to address precedented targets with the possibility of improving on such features as safety and durability of response.