MicroRNA Targets for Asthma Therapy

Asthma is a chronic inflammatory obstructive lung disease that is stratified into endotypes. Th2 high asthma is due to an imbalance of Th1/Th2 signaling leading to abnormally high levels of Th2 cytokines, IL-4, IL-5, and IL-13 and in some cases a reduction in type I interferons. Some asthmatics express Th2 low, Th1/Th17 high phenotypes with or without eosinophilia. Most asthmatics with Th2 high phenotype respond to beta-adrenergic agonists, muscarinic antagonists, and inhaled corticosteroids. However, 5-10% of asthmatics are not well controlled by these therapies despite significant advances in lung immunology and the pathogenesis of severe asthma. This problem is being addressed by developing novel classes of anti-inflammatory agents. Numerous studies have established efficacy of targeting pro-inflammatory microRNAs in mouse models of mild/moderate and severe asthma. Current approaches employ microRNA mimics and antagonists designed for use in vivo. Chemically modified oligonucleotides have enhanced stability in blood, increased cell permeability, and optimized target specificity. Delivery to lung tissue limits clinical applications, but it is a tractable problem. Future studies need to define the most effective microRNA targets and effective delivery systems. Successful oligonucleotide drug candidates must have adequate lung cell uptake, high target specificity, and efficacy with tolerable off-target effects.