MicroRNA Therapeutics in Asthma – MITHRA

The respiratory epithelium protects the body against many inhaled noxious agents (toxic particles or pathogens). The sterility of the airways is obtained for deep part through an efficient mucociliary clearance: Hundreds motile cilia located at the apical surface of multiciliate airway epithelial cells beat in a coordinated manner, and expel inhaled exogenous components, previously trapped by mucus. In several chronic airway diseases like asthma, frequent aggressions of the respiratory tract result in a loss of multiciliate cells together with mucus-secreting cell hyperplasia. The loss of multiciliate cells associated with an overproduction of mucus leads to impaired mucociliary clearance, associated with the development of chronic respiratory insufficiency. Understanding the mechanisms underlying the biosynthesis of motile cilia and the restoration of an ad hoc mucociliary respiratory epithelium is an important issue in cell biology, with obvious biomedical relevance. Recent observations, including by ourselves, suggest that chronic respiratory diseases such as asthma may benefit from therapeutic use of microRNAs (miRNAs). MiRNAs are endogenous small non-coding RNAs which regulate many genes and biological networks. The modulation of expression of a single miRNA in lungs is likely to have major effects, including in terms of therapeutic impact. In this perspective, we demonstrated that the family of miRNA miR-449 plays a key role in the biogenesis of motile cilia by directly repressing the Delta / Notch signaling pathway in the multiciliate cell precursors (Marcet et al, 2011). Our results have unravelled a conserved mechanism in which the Notch signaling system has to be inhibited by miR-449 in order to promote the biosynthesis of motile cilia in epithelial cells. Based on these data, the main objective of MITHRA will be to validate, at a pre-clinical level, the use by inhalation of exogenous miR-449 as a therapeutic approach in asthma to prevent or revert mucus hypersecretion and mucous hyperplasia by facilitating the production of motile cilia by respiratory epithelial cells. We anticipate from our results, protected by Patent No. 09/03723, PCT/FR2010/000539, the development of innovative approaches using miRNAs in the field of chronic respiratory diseases associated with defective cilia.