Antisense MicroRNA Therapy of Airway Remodeling in House Dust Mite–sensitized Mice

There is compelling need for mechanistically novel antiinflammatory and antiremodeling drugs for therapy of severe asthma. Our goal is to develop systemically administered agents that provide long-acting suppression and reversal of lung inflammation, mucosal metaplasia, and airway structural cell remodeling. To inhibit remodeling, microRNA (miR)-145 was targeted because it is a key regulator of structural cell differentiation and inflammation. An antisense, locked nucleic acid/DNA oligonucleotide complementary to nucleotides 2–16 of hsa-miR-145–5p (anti–miR-145) was delivered to the lungs via a novel lipid nanoparticle administered intravenously. After sensitization with house dust mite (HDM), 2 cohorts of 10 mice were treated with dextrose or anti–miR-145 nanoparticles (2 mg/kg, intravenously, on Days 13, 15, and 17). A third cohort of control mice was not sensitized to HDM and was not treated with anti–miR-145. Bronchoalveolar lavage (BAL) was performed on Day 18, and lungs were fixed with formalin. There was significant eosinophilia of the BAL fluid after challenge with HDM, and increased CD68 immunostaining of tissue sections, which verified the effectiveness of HDM challenge. Airway and vascular wall remodeling and increased mucin-producing cells were observed in HDM-challenged animals. Mice treated with anti–miR-145 showed reduced BAL eosinophilia, reduced obstructive airway remodeling, reduced mucosal metaplasia, and reduced CD68 immunoreactivity. Anti–miR-145 delivered intravenously distributed to most cells in the lung parenchyma, as shown by in situ hybridization. Antagonizing the function of miR-145 in the lung significantly reduces obstructive remodeling in a short-term HDM mouse model of asthma. These results also establish the biodistribution and efficacy of anti–miR-145 delivered via the blood compartment, which bypasses obstructed airways that can limit distribution and efficacy of inhaled antisense oligonucleotides.