mRNA-Mediated Gene Supplementation of Toll-Like Receptors as Treatment Strategy for Asthma In Vivo

Franziska Zeyer; Benedikt Mothes; Clara Will; Melanie Carevic; Jennifer Rottenberger; Bernd Nürnberg; Dominik Hartl; Rupert Handgretinger; Sandra Beer-Hammer; Michael S D Kormann

doi:10.1371/journal.pone.0154001

mRNA-Mediated Gene Supplementation of Toll-Like Receptors as Treatment Strategy for Asthma In Vivo

PLoS One. 2016 Apr 21;11(4):e0154001. doi: 10.1371/journal.pone.0154001. eCollection 2016.

Affiliations

¹ Department of Pediatrics I - Pediatric Infectiology and Immunology - Translational Genomics and Gene Therapy, University of Tübingen, Tübingen, Germany.
² Department of Pharmacology and Experimental Therapy and ICePhA, University of Tübingen, Tübingen, Germany.

Abstract

Asthma is the most common chronic disease in childhood. Although several therapeutic options are currently available to control the symptoms, many drugs have significant side effects and asthma remains an incurable disease. Microbial exposure in early life reduces the risk of asthma and several studies have suggested protective effects of Toll-like receptor (TLR) activation. We showed previously that modified mRNA provides a safe and efficient therapeutic tool for in vivo gene supplementation. Since current asthma drugs do not take patient specific immune and TLR backgrounds into consideration, treatment with tailored mRNA could be an attractive approach to account for the patient's individual asthma phenotype. Therefore, we investigated the effect of a preventative treatment with combinations of Tlr1, Tlr2 and Tlr6 mRNA in a House Dust Mite-induced mouse model of asthma. We used chemically modified mRNA which is-in contrast to conventional viral vectors-non-integrating and highly efficient in gene transfer. In our study, we found that treatment with either Tlr1/2 mRNA or Tlr2/6 mRNA, but not Tlr2 mRNA alone, resulted in better lung function as well as reduced airway inflammation in vivo. The present results point to a potentially protective effect of TLR heterodimers in asthma pathogenesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Asthma / therapy*
Disease Models, Animal*
Female
Mice
Mice, Inbred BALB C
Pyroglyphidae / pathogenicity
RNA, Messenger / genetics*
Toll-Like Receptors / genetics*

Substances

RNA, Messenger
Toll-Like Receptors

Grants and funding

This work was supported by the Deutsche Forschungsgemeinschaft (DFG) (www.dfg.de, DFG KO 4258/2-1, to MSDK), by the University of Tübingen with a fortüne grant (no. 2201-0-0) and an IZKF graduate program grant (to FZ), by the European Respiratory Society (Maurizio Vignola Award, to MSDK), by the Gesellschaft für Pulmonale Pneumologie (Klosterfrau grant, to MSDK), in part the Interfaculty Center for Pharmacogenomics and Drug Research (ICEPHA Twinning Grant 22-0-0, to SBH), and in part by the DFG (to BN and SBH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.