Sense and Antisense: Therapeutic Potential of Oligonucleotides and Interference RNA in Asthma and Allergic Disorders

Abstract

Advances in our understanding of asthma pathogenesis and delineation of the human genome project are yielding novel candidate targets for therapeutic intervention. In parallel with target identification, the past decade has produced novel approaches to normalizing expression genes that are upregulated in disease processes. Single-stranded antisense oligonucleotides and double-stranded short-interfering RNA molecules, which specifically mark target transcripts for degradation, are being investigated for their ability to modulate disease processes. In both cases, the targets are RNA transcripts, and not protein; therefore, all types of molecular gene products can be inhibited, including historically undrugable species such as transcription factors and phosphatases. Various RNA interference strategies have been successfully tested in vitro and in animal models of disease, and data is beginning to accumulate from human clinical trials.EPI-2010, a 21-mer phosphorothioate against the adenosine A1 receptor promoter region,has completed preclinical pharmacology testing and its initial clinical trials. The rationale for EPI-2010 is that overactivity of the adenosine signaling pathway in asthmatic lungs contributes to airway inflammation and hyperresponsiveness. Phase I/IIa clinical trials have shown EPI-2010 to be safe and well-tolerated, with modest indications of efficacy in patients with mild asthma.

Inhibitory Effect of Antisense Oligonucleotide Targeting TIMP-2 on Immune-Induced Liver Fibrosis

“…ASON-mRNA duplex formation induces RNase H activation, which degrades mRNA. Thus, the synthesis of the protein encoded is blocked [21,22]. At present, 17 oligonucleotide drugs have now progressed through phase I clinical trials.…”

Adenosine induces airway hyperresponsiveness through activation of A3 receptors on mast cells

“…In addition, although A 1 receptors have also been shown to partially mediate adenosine-induced bronchoconstriction through a mast cell-independent pathway, targeting the A 1 receptor gene in human beings with asthma has been largely ineffective. 16,19,33,34 These observations suggest that endogenous adenosine may affect airway pathophysiology in ways other than eliciting bronchoconstriction. In this study, we have discovered that adensosine produces AHR in mice.…”

A Multi-Targeted Antisense Oligonucleotide-Based Therapy Directed at Phosphodiesterases 4 and 7 for COPD

“…Although demonstrating efficacy in vitro and in animal models (Ball et al 2004), EPI 2010 failed in later clinical studies to demonstrate efficacy to improve lung function in asthmatics. With the more recent understanding of the role the different adenosine receptors have in asthma (Brown et al 2008), it could be argued that the absence of clinical efficacy for EPI 2010 could either be a result of targeting the wrong adenosine receptor or perhaps the need to combine it with other adenosine receptor inhibitors.…”