Biotechnological development of targeted microRNA therapeutics
Final Report Abstract
In the first part of this DFG funded research project I developed a unique, highly sensitive and non-invasive imaging approach for the detection of minimal cardiac ischemia using PET-imaging of activated platelets. This project is of high clinical relevance as the described method has the potential to detect undiagnosed ischemia and coronary artery disease. This highly sensitive detection of ischemia could be used in exercise stress testing and could also change the clinical path of patients presenting with angina pectoris and thus overall reduce the number of undiagnosed coronary artery disease patients and ultimately the number of myocardial infarctions. Aim of the second and third part of this research project was to develop new targeted therapeutics by coupling effector molecules with targeted single-chain antibodies. This biotechnological approach should allow an effective therapy with minimal side effects. The last two presented research projects focused on the characterisation and validation of the two platelet-targeted therapeutics, Tand-scFvSca-1/GPIIbIIIa and targeted-CD39 to treat myocardial infarction. The outcomes of the second research project demonstrate that non-invasive administration of PBMCs pre-treated with Tand-scFvSca-1/GPIIbIIIa reduces leukocyte infiltration into the heart, enhances neovascularisation, decreases necrosis and most importantly preserves myocardial function after ischemia/reperfusion injury. Thus, administration of PBMCs pre-treated with Tand-scFvSca-1/GPIIbIIIa is a new, potentially promising therapeutic strategy to treat acute myocardial infarction. The last research project demonstrates that platelet-targeted administration of CD39 improves cardiac systolic function, decreases infarct size and enhances neovascularisation 28 days after ischemia/reperfusion injury. Targeted-CD39 treatment does not reduce cell infiltration, but it increases significantly the amount of infiltrating T-cells and mast cells into the heart. Taken together, administration of targeted-CD39 has the potential to treat patients with acute myocardial infarction without causing bleeding complications or other side effects.
Publications
- Homing peripheral blood mononuclear cells by bispecific single-chain diabody GPIIbIIIa/Sca-1 modulates inflammation and preserves myocardial function after transient ischemia in mice. Clin Res Cardiol 104, Suppl 1, April 2015, P720
M. Ziegler, V. Ching, X. Wang, K. Alt, E. Leitner, C.E. Hagemeyer, K. Peter
- Molecular Imaging of Activated Platelets using Positron Emission Tomography: A Novel, Highly Sensitive Detection Method for Cardiac Ischemia, Circulation. 2015;132:A13792
M. Ziegler, K. Alt, C.E. Hagemeyer, K. Peter
- Highly Sensitive Detection of Minimal Cardiac Ischemia using Positron Emission Tomography Imaging of Activated Platelets. Scientific Reports volume 6, Article number: 38161 (2016)
M. Ziegler, K. Alt, B.M. Paterson, P. Kanellakis, A. Bobik, P.S. Donnelly, C.E. Hagemeyer, K. Peter
(See online at https://doi.org/10.1038/srep38161)
