Project Details
Projekt
Impact of the long non-coding RNA meg3 on unloading and repair during cardiac remodeling
Subject Area
Cardiology, Angiology
Cardiac and Vascular Surgery
Cardiac and Vascular Surgery
Term
from 2016 to 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 286251789
The implantation of mechanical pumps to support cardiac function isoften the only remaining therapeutic treatment option for themanagement of end stage heart failure. Left ventricular assist devicesare frequently used as bridge-to-transplantation, to extend thepatient’s life until a donor organ is available. The ideal scenario,however, is that such a cardiac unloading therapy leads to functionalrecovery of the diseased heart. Unfortunately, this is observed in only5% of the patients which emphasizes the urgent need for novel,adjuvant therapies during unloading, aiming to e.g. preventpathological hypertrophy or cardiac fibrosis. In this regard, ourprevious work identified two long non-coding RNAs (lncRNAs) aspotential therapeutic targets, lncRNAs H19 and meg3. During the firstfunding period we demonstrated anti-hypertrophic functions of an H19gene therapy in the TAC mouse model. We further found that the(dys)-regulation of this highly conserved lncRNA under cardiac stressand disease conditions is paralleled in porcine and human hearts.Consequently, a patent for the therapeutic use of H19 was filed andgranted. This patent was recently licensed from Hannover MedicalSchool to the biotech SME Cardior to pursue translation of H19 intothe clinic. In contrast to the therapeutic effects of H19 which aremainly attributed to its anti-hypertrophic function in cardiomyocytes,inhibition of meg3 exhibits rather anti-fibrotic effects in the mouseheart. Indeed, our preclinical data demonstrate similar effects inprimary human cardiac fibroblasts. Thus, the aim in the secondfunding period is, in extended close collaboration between the twoapplicants Thum and Cebotari, to translate these results to human exvivomodels and to the porcine TAC model as a clinically relevantanimal model, to study the in vivo effects of a meg3 therapy duringcardiac unloading. The work programme is also tightly connected toother projects within this KFO. For example, effectiveness of meg3inhibitors will first be tested in the organ care system (OCS) in orderto select the best adjuvant therapeutic option during unloading in theporcine model developed by Cebotari within the first funding period. Incomplementary studies using primary human cardiac fibroblasts, wewill validate and further extend the meg3 mechanistic studies throughpromoter analysis and specific ChIP-Seq and ATAC-Seq experiments.Finally, we will perform a combination of cardioprotective therapies(meg3 & Tert) in the mouse TAC model aiming to identify noveldisease target. In sum, our overarching goal is and remains thepreclinical development of adjuvant therapies for improved functionalrecovery of the heart during mechanic unloading.
DFG Programme
Clinical Research Units
