title: RASONs: a novel antisense oligonucleotide therapeutic approach for asthma.
abstract: 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 A(1) 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 A(1) 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.
authors.affiliation: Epigenesis Pharmaceuticals, Inc., Cranbury, New Jersey 08512, USA. asandrasagra@EpiGene.com
authors.forename: A
authors.initials: A
authors.lastname: Sandrasagra
authors.forename: L
authors.initials: L
authors.lastname: Tang
authors.forename: S A
authors.initials: SA
authors.lastname: Leonard
authors.forename: K
authors.initials: K
authors.lastname: Teng
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: J C
authors.initials: JC
authors.lastname: Mannion
authors.forename: J W
authors.initials: JW
authors.lastname: Nyce
mesh_terms: D000241:Adenosine / Q000502:physiology; D001249:Asthma / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D005786:Gene Expression Regulation; D006801:Humans; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D018047:Receptors, Purinergic P1 / Q000502:physiology
chemical_list: D016376:Oligonucleotides, Antisense; D018047:Receptors, Purinergic P1; D000241:Adenosine