Current asthma therapy targets acute bronchoconstriction and chronic inflammation, but does not reverse occlusive airway remodeling. The lack of effect on remodeling combined with corticosteroid insensitivity and resistance to beta agonists results in a small but significant subpopulation of asthmatics who are difficult to control and who are at highest risk of fatal attacks. Thus there is compelling need for mechanistically novel anti-remodeling drugs in therapy of severe asthma. We seek to develop a novel class of systemically administered agents that provides long-acting suppression and reversal of mucosal metaplasia, inflammation and structural cell remodeling. We will address this gap in knowledge by delivering microRNA antagonists to the lungs of mice sensitized with house dust mite antigens. The function of two microRNAs (miR-145 and miR-155) with different molecular targets will be antagonized with highly sequence-specific antisense oligonucleotides. AntimiR-145 and antimiR-155 will be delivered preferentially to lung tissue by IV administration of a novel lipid nanoparticle delivery vehicle (Therasilence). We hypothesize that antagonizing key microRNA regulators of differentiation and inflammation will reduce the volume density of both immune cells and structural cells, thus stopping or reversing obstructive remodeling. The cellular processes and molecular mechanisms underlying antiremodeling effects of the miRNA antagonists will be defined in vitro using cultured human lung cells. The results will establish biodistribution, efficacy and molecular targets of a new class of anti- remodeling agents that could be effective in treating asthma in patients resistant to current drug therapy.

A significant number of asthmatics suffer from severe, debilitating and potentially fatal disease that is not well controlled by current drug therapy. For patients with severe asthma there is a compelling need for new types of drugs that stop the progression of the disease and repair the damage to the airways that occurs over time. We want to develop such drugs based on naturally occurring small ribonucleic acid molecules. The new agents will be lung- targeted molecules that effectively prevent symptoms of severe, drug-resistant asthma.