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

心血管疾病是全世界死亡的主要原因，迫切需要新的治疗干预措施。心脏应激如心肌梗死可导致心脏重构和心力衰竭。一个新的药物实体是寡核苷酸疗法（ONTs），如mirna或长链非编码rna （lncRNAs）的抑制剂。我们已经发现了一种有效靶向lncRNA meg3的ONT，从而减少心脏应激动物的心脏重塑和纤维化。然而，在药物开发过程中，ONTs众所周知具有脱靶效应，并在许多器官中诱发毒理学效应。因此，本提案的目的是全面评估几种不同的新型抗纤维化lncRNA meg3抑制剂对行为、运动、感觉和认知功能以及血液中应激标志物变化的影响，这些变化将在实验过程中测量。此外，我们将通过访问该联盟中可用的各种动物疾病模型，开发和验证一套新的应激敏感标记循环mirna。这些方法和参数的收集可能会确定最可靠和最适合的严重性评估测试，特别是在寡核苷酸抑制剂开发领域，这是大学和制药工业日益增加的研究领域。我们预计，产生和验证基于外周血测量的新型miRNA应激敏感测试系统的广泛方法将增加对常见窘迫标志物的额外了解。

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.