Sherry A. Leonard

Discovery and development of respirable antisense therapeutics for asthma.

Respirable antisense oligonucleotides (RASONs) represent a novel class of respiratory therapeutic molecules with the potential to specifically address the challenges posed by the successes of the Human Genome Program, namely, the need to rapidly identify the critical pulmonary disease-relevant drugable targets from the vast pool of 30,000-40,000 human genes and to discover and develop drugs that specifically attack these targets. We have shown that EPI-2010, a RASON targeting the adenosine A1 receptor, a G-protein coupled receptor that has been implicated in the regulation of three major determinants of asthma, can be delivered directly to the target disease tissue as an aerosol formulation. In vivo efficacy, absorption, distribution, metabolism, and excretion (ADME), and safety studies of inhaled EPI-2010 employing animal models of human asthma suggest that the RASON approach enables the specific delivery of efficacious, safe, and long-acting doses of phosphorothioate oligonucleotides to the respiratory tract. Moreover, these data indicate that RASONs truly have the potential to address the respiratory drug discovery bottleneck of the postgenomic era, that is, the ability to rapidly validate disease targets and develop pulmonary disease therapeutics for these validated targets.

RASONs: a novel antisense oligonucleotide therapeutic approach for asthma

Inhalation based approaches enable the local delivery of antisense oligonucleotides (ASONs) to the respiratory tract and thus facilitate the ability of ASONs to target and modulate the activity of discordantly expressed respiratory disease genes. Studies involving EPI-2010, a respirable antisense oligonucleotide (RASON), targeting the adenosine A1 receptor, a G-protein-coupled-receptor (GPCR) that plays an important role in the aetiology of asthma, demonstrate that ASON therapeutics can be delivered directly to the lung as an aerosol. EPI-2010 has been shown to inhibit adenosine A1 receptor expression and significantly improve allergen-induced airway obstruction and bronchial hyper-responsiveness in animal models of human asthma. Absorption, tissue distribution, metabolism and excretion (ADME) and safety studies of aerosolised EPI-2010 suggest that phosphorothioate RASONs can be delivered to target respiratory tissues in low, safe, efficacious and long-acting doses. This supports the concept that RASONs offer the potential to address a variety of respiratory targets including those for which approaches employing systemic distribution and systemic bioavailability of the therapeutic agent may be undesirable. In addition, our studies with EPI-2010 indicate that the RASON approach may represent a technology that is uniquely positioned to address the challenges of the post-genome era in respiratory drug discovery, since it enables simultaneous in vivo target validation and antisense therapeutic discovery in an accelerated timeframe.