Biotechnological development of targeted microRNA therapeutics

• Applicant: Melanie Ziegler, Ph.D.
• Subject Area: Cardiology, Angiology
• Term: from 2013 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 241815696

Cardiovascular diseases are the leading cause of death worldwide. Especially atherosclerosis-induced diseases like myocardial infarction and stroke show a high mortality and morbidity rate. To improve the expectancy and quality of life the aim of the proposed research project is the development of bifunctional antibodies, consisting of micro-RNA and targeted single-chain antibodies.A promising, new and innovative approach is the therapeutic use of micro-RNAs. It has been shown repeatedly that cardiovascular diseases are associated with changes in miRNA levels. The cardiovascular pathophysiology can be changed positively by targeted modulation of individual miRNAs. MiR-126 and miR-155 have an important influence on atherogenesis. The main challenge in therapeutic intervention is a targeted delivery of miRNA, with the aim to avoid generalized side effects. To achieve this in the following proposal miRNA will be coupled to targeted antibodies. Therefore, targeted single-chain antibodies against VCAM-1 and LIBS will be used. These antibodies bind specifically to inflammatory endothelium (VCAM-1), activated platelets (LIBS to GPIIb/IIIa) and atherosclerotic plaques (VCAM-1 and LIBS). By this antibody-mediated enrichment, therapeutically effective miRNAs accumulate at the desired target without systemic and generalized effects. In this approach, miR-126 or the antagomir anti-miR-155 should modulate the protein production and thereby influence positively the process of atherogenesis. The bifunctional antibodies will be tested for their functionality in vitro using a flow chamber system, flow cytometry, detection of protein expression and a TNF-alpha ELISA. Finally, the anti-inflammatory, therapeutic potential of the bifunctional antibodies will be characterized by an in vivo mouse model of neointima formation after wire-induced carotid injury and a mouse model of atherosclerosis. In the submitted proposal an innovative, new class of therapeutics will be established by coupling miR-therapeutics with targeted single-chain antibodies. This therapeutics should allow an effective therapy with minimal side effects.

• DFG Programme: Research Fellowships
• International Connection: Australia
• Host: Professor Karlheinz Peter, Ph.D.