The future of antisense oligonucleotides in the treatment of respiratory diseases

Abstract

Antisense oligonucleotides (ASO) are short synthetic DNA molecules designed to inhibit translation of a targeted gene to protein via interaction with messenger RNA. More recently, small interfering (si)RNA have been developed as potent tools to specifically inhibit gene expression. ASO directed against signaling molecules, cytokine receptors, and transcription factors involved in allergic immune and inflammatory responses, have been applied in experimental models of asthma and demonstrate potential as therapeutics. Several ASO-based drugs directed against oncogenes have been developed for therapy of lung cancer, and some have recently reached clinical trials. ASO and siRNA to respiratory syncytial virus infection have demonstrated good potential to treat this condition, particularly in combination with an antiviral drug. Although ASO-based therapeutics are promising for lung diseases, issues of specificity, identification of correct molecular targets, delivery and carrier systems, as well as potential adverse effects must be carefully evaluated before clinical application.

Fig. 1

Phosphorothioate backbone modification of oligonucleotides that inhibits nuclease degradation of antisense.

Fig. 2

Major mechanisms of action of antisense oligonucleotides (ASO). (a) Activation of endonuclease RNAse H, leading to messenger (m)RNA degradation. (b) Inhibition of the ribosomal complex formation via steric blocking. (c) Inhibition of mRNA splicing.

Fig. 3

Hypothetical model of RNA interference. (a) When introduced into a cell, double-stranded (ds)RNA is cleaved into small interfering (si)RNAs by a Dicer nuclease in an adenosine triphosphate (ATP)-dependent process. (b) Duplex siRNAs are recruited by several intracellular proteins, forming the RNA-induced silencing complex (RISC). (c) Unwinding of duplex siRNA occurs in an ATP-dependent manner. (d) The antisense strand of the siRNA binds to the messenger (m)RNA. (e) Activation of nuclease activity leads to degradation of the target mRNA. ADP = adenosine diphosphate; P = phosphate.

Table I

Adverse effects of antisense therapy

Table II

Clinically relevant targets of antisense-based therapy in respiratory diseases