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

在小型和大型动物模型中测试非编码 RNA 寡核苷酸疗法的不良副作用

• 批准号: 329771426
• 负责人: Professor Dr. Thomas Thum, Ph.D.
• 金额: --
• 依托单位: Institut für Molekulare und Translationale Therapiestrategien
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/329771426?language=en
• 关键词: Testing; unwanted; side; effects; noncoding

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.

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。心肌梗塞等心脏应激会导致心脏重塑和心力衰竭。一种新的药物实体是寡核苷酸疗法 (ONT)，例如 miRNA 或长非编码 RNA (lncRNA) 抑制剂。我们已经鉴定出一种有效靶向 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，众所周知，ONT 具有脱靶效应，并会在许多器官中引起毒理学作用。因此，本提案的目的是彻底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压力标记物变化的影响，这些变化将在治疗过程中测量。实验。此外，我们将通过访问该联盟中可用的各种动物疾病模型来开发和验证一组新型压力敏感循环 miRNA 标记物。这些方法和参数集合可能会确定最稳健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，这是大学和制药行业日益增长的研究领域。我们预计，基于外周血测量来生成和验证新型 miRNA 压力敏感测试系统的广泛方法将增加关于常见压力标志物的更多知识。

项目成果

A novel multi-parametric analysis of non-invasive methods to assess animal distress during chronic pancreatitis

一种新的非侵入性方法多参数分析，用于评估慢性胰腺炎期间动物的痛苦

• DOI: 10.1038/s41598-019-50682-3
• 发表时间: 2019-10-01
• 期刊: Scientific Reports
• 影响因子: 4.6
• 作者: A. Abdelrahman;S. Kumstel;Xianbin Zhang;Marie Liebig;E. H. U. Wendt;Johanna Eichberg;R. Palme;T. Thum;B. Vollmar;D. Zechner
• 通讯作者: D. Zechner

Remote vitals monitoring in rodents using video recordings.

使用视频记录远程监测啮齿动物的生命体征

• DOI: 10.1364/boe.10.004422
• 发表时间: 2019
• 期刊: Biomedical optics express
• 影响因子: 3.4
• 作者: Kunczik; J.; C.B. Pereira; L. Zieglowski; R. Tolba; L. Wassermann; C. Häger; A. Bleich; H. Janssen; T. Thum;M. Czaplik
• 通讯作者: M. Czaplik

Pharmacokinetic Studies of Antisense Oligonucleotides Using MALDI-TOF Mass Spectrometry

使用 MALDI-TOF 质谱法研究反义寡核苷酸的药代动力学

• DOI: 10.3389/fphar.2020.00220
• 发表时间: 2020
• 期刊: Frontiers in Pharmacology
• 影响因子: 5.6
• 作者: Herkt M; Foinquinos A; Batkai S; Thum T; Pich A
• 通讯作者: Pich A

Perspective review of optical imaging in welfare assessment in animal-based research

光学成像在动物研究福利评估中的透视综述

• DOI: 10.1117/1.jbo.24.7.070601
• 发表时间: 2019
• 期刊: Journal of Biomedical Optics
• 影响因子: 3.5
• 作者: Pereira; C.; J. Kunczik; A. Bleich; C. Haeger; F. Kiessling; T. Thum; R. Tolba; U. Lindauer; S. Treue;M. Czaplik
• 通讯作者: M. Czaplik

Remote Welfare Monitoring of Rodents Using Thermal Imaging

使用热成像对啮齿动物进行远程福利监测

• DOI: 10.3390/s18113653
• 发表时间: 2018-10-28
• 期刊: Sensors (Basel, Switzerland)
• 作者: Pereira CB;Kunczik J;Zieglowski L;Tolba R;Abdelrahman A;Zechner D;Vollmar B;Janssen H;Thum T;Czaplik M
• 通讯作者: Czaplik M