Modified-mRNA Delivery of Evasins
- 1 August 2018 to 31 March 2019
- Awards: Pump-priming Awards
Novel anti-inflammatory proteins called evasins have been identified from tick saliva1. These proteins block chemokines with a unique “one-agent-to many-target” mechanism of action making them potentially beneficial in treatment of inflammatory diseases driven by multiple chemokines1.
Our goals are to develop evasins as therapeutics for cardiovascular inflammation, including myocarditis, myocardial infarction, and ischemia-reperfusion injury in the heart. Key challenges have been a) to produce large amounts of endotoxin-free purified evasin protein; b) to prolong the half-life in vivo; c) achieve high local concentrations of evasin in the target organ.
To overcome the above challenges we will use a recent advance which has seen the development of modified mRNA (mod-mRNA) delivery of biologicals to the myocardium2-5, resulting in endogenous endotoxin free and continuous local production of the biologic in the target organ.
We therefore propose to develop the targeted delivery of evasins encoded as modified mRNA molecules to the heart.
1. Bonvin, P., Power, C.A. & Proudfoot, A.E. Evasins: Therapeutic Potential of a New Family of Chemokine-Binding Proteins from Ticks. Front Immunol 7, 208 (2016).
2. Turnbull, I.C. et al. Myocardial Delivery of Lipidoid Nanoparticle Carrying modRNA Induces Rapid and Transient Expression. Mol Ther 24, 66-75 (2016).
3. Sultana, N. et al. Optimizing Cardiac Delivery of Modified mRNA. Mol Ther 25, 1306-1315 (2017).
4. Kondrat, J., Sultana, N. & Zangi, L. Synthesis of Modified mRNA for Myocardial Delivery. Methods Mol Biol 1521, 127-138 (2017).
5. Turnbull, I.C., Eltoukhy, A.A., Anderson, D.G. & Costa, K.D. Lipidoid mRNA Nanoparticles for Myocardial Delivery in Rodents. Methods Mol Biol 1521, 153-166 (2017).