Pharmacokinetics of RNA-based therapeutics
Team: Petros Avramopoulos, Deepak Ramanujam, Bernhard Laggerbauer, Saskia Rausch, Sabine Brummer
A widely employed approach to investigate microRNA function in vitro and in vivo are synthetic inhibitors (antimiRs) for these molecules. Although several chemical modifications have been invented that warrant improved pharmacodynamics and stability against nucleases, their poor membrane penetrance, tissue- or cell-specificity of antimiRs are still major problems that often obstruct progress towards therapeutic applications. The myocardium is one of the most challenging organs in this respect, but, on the other hand - as our work had shown - perhaps also one of the therapeutically most rewarding. Therefore, we aim to optimize the delivery and distribution of antimiRs against cardiac-specific miRNAs so that they show increased uptake, efficiency and specificity in vivo. For this reason, we use different chemistries of antimiRs against specific miRNAs of interest in several models of heart failure. The distribution of fluorophore-coupled antimiRs is visualized by high-resolution microscopy whereas its efficiency by quantifying the levels of the target miRNAs as well as well-established target mRNAs.
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