Testing of unwanted side effects of noncoding RNA oligonucleotide therapeutics in small and large animal models

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Cardiovascular diseases are the main cause of mortality worldwide and new therapeutic interventions are urgently needed. Cardiac stress such as myocardial infarction leads to cardiac remodelling and heart failure. A new entity of drugs are oligonucleotide therapeutics (ONTs) such as inhibitors of miRNAs or long noncoding RNAs (lncRNAs). We have identified an ONT targeting the lncRNA meg3 effectively, thus reducing cardiac remodeling and fibrosis of cardiac stressed animals. However, during drug development, ONTs are well known to have off-target effects and to induce toxicological effects in many organs. Thus, the aim of this proposal is to thoroughly assess the effects of several different novel anti-fibrotic lncRNA meg3 inhibitors on changes in behaviour, motor, sensory and cognitive function as well as stress markers in the blood that will be measured during the course of the experiment. In addition, we will develop and validate a novel stress-sensitive marker set of circulating miRNAs through access to various animal disease models available in this consortium. These approaches and collection of parameters will likely identify the most robust and best suited severity assessment tests especially in the field of oligonucleotide inhibitor development, an increasing research field in universities but also pharmaceutical industry. We anticipate that the broad approach to generate and validate a novel miRNA stress-sensitive test system based on measurements in peripheral blood will add additional knowledge on common markers for distress.