Modified mRNA encoding Foxp3 protects against allergic asthma in mice by rebalancing T helper cell responses through an IL-23 / IL-17A-dependent mechanism

Chemically modified mRNA has recently shown life-saving efficacy in a murine model of a rare, genetic lung disease, Surfactant Protein-B deficiency, by inducing therapeutic levels of protein expression while circumventing the threat of genomic integration often associated with viral vectors (Kormann et al, Nat Biotechnol. 2011 Feb; 29(2):154-7). To translate this novel therapeutic tool into a high prevalence disease model, we investigated whether modified mRNA could restore immune balance and alleviate disease severity in Th2-driven allergic asthma. We show that intratracheal delivery of modified mRNA coding for the regulatory T cell factor Foxp3 rebalanced pulmonary T helper cell responses, modulated innate immune cell recruitment, and protected from allergen-induced tissue inflammation and goblet cell metaplasia. Protection against asthma was achieved following delivery of modified mRNA either before or after the onset of allergen challenge, demonstrating its potential as both a preventative and a therapeutic. Mechanistically, Foxp3 upregulation was critical in downregulating IL-23 and IL-17 production, and recombinant IL-23 or IL-17 expression during challenge abolished protection conferred by Foxp3 mRNA. Taken together, our results provide evidence that chemically modified Foxp3 mRNA protects against allergic asthma in vivo, which may pave the way for considering modified mRNA as a safe therapeutic tool for the treatment of asthma, allergy and beyond.