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

• Applicant: Professor Thomas Thum, Ph.D.
• Subject Area: Cardiology, Angiology ; Sensory and Behavioural Biology
• Term: from 2017 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 321137804

• Final Report Year: 2020

Final Report Abstract

This project had mainly 2 parts. As cardiovascular diseases are the main cause of mortality worldwide and new therapeutic interventions are urgently needed we focused on an ONT targeting the lncRNA meg3, and test potential effects on bahaviour in cardiac stressed animals. Due to well-known off-target effects of ONTs we initially used a MTT based screening set-up to test for cytotoxicity and identified one candidate for in vivo testing. This candidate was further checked for behavioral effects in mice during automatic wheel running after MI. Meg3 treatment improved wheel running behavior from mice after MI, but this was not statistically significant. However, during echo measurement under anesthesia it could be proved that respiratory rate can be accessed via contactless non invasive thermal imaging. Our second aim was to identify circulating miRNAs as stress sensitive markers in various animal disease models. Therefore we chose three research areas (inflammatory bowel disease, epilepsy and gastrointestinal diseases like pancreatitis, bile duct ligation and pancreatic cancer). For each disease a subgroup of probes was randomly selected for global miRNA screening and selected candidates were validated throughout whole sample quantity per research area. With this setup, we could identify animal model specific miRNAs (IBD: mir-1951, miR-2183, miR-138, miR-322, miR-1944, miR-1951 and miR-2183; epilepsy model: miR-203 and miR-429; gastrointestinal diseases: miR-132, mir-375, mir-30b and mir-203). In the future these identified sets of miRNAs will help researchers to detect the levels on stress in animals, the overall main goal of this grant.

Publications

• (2018). Circulating non-coding RNAs in biomarker-guided cardiovascular therapy: a novel tool for personalized medicine? Eur Heart J. 40(20):1643-1650
  de Gonzalo-Calvo D, Vea A, Bär C, Fiedler J, Couch LS, Brotons C, Llorente-Cortes V, Thum T
  
• 2018. Remote Welfare Monitoring of Rodents Using Thermal Imaging. Sensors (Basel) 18(11). pii: E3653
  Pereira, C. B., J. Kunczik, L. Zieglowski, R. Tolba, A. Abdelrahman, D. Zechner, B. Vollmar, H. Janssen, T. Thum, and M. Czaplik
  
• 2019. Perspective review of optical imaging in welfare assessment in animal-based research. Journal of biomedical optics 24: 1-11
  Pereira, C., J. Kunczik, A. Bleich, C. Haeger, F. Kiessling, T. Thum, R. Tolba, U. Lindauer, S. Treue, and M. Czaplik
  
• 2019. Remote Vitals Monitoring in Rodents Using Video Recordings. Biomed. Opt. Express 10: 4422-4436
  Kunczik, J., C.B. Pereira, L. Zieglowski, R. Tolba, L. Wassermann, C. Häger, A. Bleich, H. Janssen, T. Thum, and M. Czaplik
  
• A novel multi-parametric analysis of non-invasive methods to assess animal distress during chronic pancreatitis. Scientific reports. 2019
  Abdelrahman, Kumstel, Zhang, Liebig, Wendt, Eichberg, Palme, Thum, Vollmar, Zechner
  
• (2020). Pharmacokinetic Studies of Antisense Oligonucleotides Using MALDI-TOF Mass Spectrometry. Front Pharmacol. 11:220
  Herkt M, Foinquinos A, Batkai S, Thum T, Pich A
  
• miR-21 and NT-proBNP Correlate with Echocardiographic Parameters of Atrial Dysfunction and Predict Atrial Fibrillation. J Clin Med. 2020 Apr 14;9(4). pii: E1118
  Sieweke JT, Pfeffer TJ, Biber S, Chatterjee S, Weissenborn K, Grosse GM, Hagemus J, Derda AA, Berliner D, Lichtinghagen R, Hilfiker-Kleiner D, Bauersachs J, Bär C, Thum T, Bavendiek U