“We can still expect a lot there” – an Interview about RNA science and therapies
The Federal Agency for Civic Education (Bundeszentrale für politische Bildung/bpb) regularly publishes information on political issues for everyone. "Aus Politik und Zeitgeschichte (APuZ)" is one of the bps‘s magazines, which is published online and as supplement of the newspaper “Das Parlament”.
In the recent issue “Gentechnik”, Professor Thomas Thum gave an interview about RNA, the current RNA research fields and therapeutic possibilities using RNA. With regard to the latter, RNA therapeutics against cancer, rare diseases and heart failure need to be mentioned.
Professor Thum and his team focus on developing RNA therapeutics against heart failure. The first candidate, microRNA-132, has successfully passed the first phase of clinical trials and undergoes the second phase, now. Another candidate, a circular RNA, has been identified, which plays an important role in regulating chemotherapy-mediated cardiotoxicity. Professor Thum believes that “we can still expect a lot” regarding RNA therapeutic strategies.
Please find the whole interview here: "Wir dürfen da noch sehr viel erwarten" | bpb.de
The Thum Lab has officially joined Twitter
Updates on our most recent publications, talks, and lab activities in the cardiology and RNA world can be found on Twitter @Thum_Lab, now.
Accelerating cardiovascular research: recent advances in translational 2D and 3D heart models
As the prevalence of cardiovascular diseases increases, so does the need for sufficient in vitro systems that recapitulate the complex human heart. Our recent review, first-authored by IMTTS researcher Elisa Mohr and published in the “European Journal of Heart Failure”, therefore summarizes the basic principles of cardiomyocyte monolayer cultivation as well as the 3D culture systems of cardiac spheroids and organoids, engineered cardiac microtissues, bioprinted cardiac tissues and ex vivo living myocardial slices. In addition, we highlighted latest advances of these heart models that aim to bridge the gap of in vitro and in vivo systems.
Please find our review here: https://onlinelibrary.wiley.com/doi/10.1002/ejhf.2631
Nature Review Cardiology highlights IMTTS’ publication
We are glad that Nature Review Cardiology selected our recently published article about circular RNAs as novel therapeutic strategy against doxorubicin-induced cardiotoxicity as a research highlight.
Please find their comment here: Circular RNA prevents doxorubicin-induced cardiotoxicity | Nature Reviews Cardiology
Original article: Lu D, Chatterjee S, Xiao K, et al. A circular RNA derived from the insulin receptor locus protects against doxorubicin-induced cardiotoxicity [published online ahead of print, 2022 Jun 27]. Eur Heart J. 2022;ehac337. doi:10.1093/eurheartj/ehac337, see: https://pubmed.ncbi.nlm.nih.gov/35758064/
News about targets in heart failure treatment
IMTTS researchers Sonja Groß, Malte Juchem, Jia Li Ye, Kevin Schmidt, Florian Waleczek, Dr. Shambhabi Chatterjee and PD Dr. Christian Bär attended the DGK symposium ‘Targets in heart failure treatment’ in Würzburg organized by AG12 and AG13 of the DGK working groups from 15-16th July 2022. The sessions covered topics in basic, translational and clinical aspects. IMTTS researchers also presented their innovative research during the poster session.
New AAV vectors for cardiac-directed gene therapy
AAV vectors are promising delivery tools for human gene therapy. However, broad tissue tropism and pre-existing immunity against natural serotypes limit their clinical use. By in vivo AAV2 peptide display library screening in a murine model of pressure overload-induced cardiac hypertrophy, IMTTS researchers Dr. Laura Rode and PD Dr. Christian Bär have identified two promising AAV capsid variants in collaboration with Prof. Dr. Hildegard Büning.
The newly identified AAV vectors are auspicious novel tools for cardiac-directed gene therapy outcompeting the reference serotype AAV9 regarding the specificity and therapeutic efficiency of in vivo cardiomyocyte transduction.
Please find out more in the original article: https://doi.org/10.1016/j.ymthe.2022.07.003
In addition, please have a look on the website of MHH Insight: https://www.mhh.de/en/presse/mhh-insight/news-detailed-view/targeting-heart-disease#
Circular RNA therapy against doxorubicin-induced cardiotoxicity
Noncoding RNA based therapy has gained a lot of focus as a potential treatment strategy for cardiovascular diseases. In another recent publication, IMTTS scientists have identified a highly species conserved circular RNA (Circ-RNA) which plays important role in regulating doxorubicin-mediated cardiotoxicity. Dr. Dongchao Lu and Dr. Shambhabi Chatterjee led this project under the supervision of Prof. Dr. Dr. Thomas Thum and PD Dr. Christian Bär.
After performing a Circ-RNA sequencing, the team came across Circ-INSR as a potential regulator of heart failure. Using animal models in vivo and a translational human induced pluripotent stem cell derived cardiomyocyte (hiPSC-CM) model in vitro, gain and loss-of-function studies for Circ-INSR were performed in the context of doxorubicin-induced heart failure. Using adeno-associated viruses (AAVs), the researchers validated that Circ-INSR overexpression exhibits protective effects against doxorubicin-induced cardiotoxicity via modulating mitochondrial function. Furthermore, these protective effects were reproducible with another novel strategy of Circ-RNA overexpression. The IMTTS research team generated the Circ-INSR mimics with the help of in vitro transcription techniques and applied an innovative circularization technology to produce these molecules for pre-clinical tests.
With this publication, we not only provide a better mechanistic understanding of the Circ-RNA mechanisms but also a novel strategy to overexpress Circ-RNAs for therapeutic options.
Please find the publication here: https://pubmed.ncbi.nlm.nih.gov/35758064/
Congratulations to Anne Bührke and Alessia Cost for successfully defending their PhD theses
IMTTS researcher Anne Bührke has successfully defended her PhD thesis entitled “Long noncoding RNAs H19 and Meg3 as therapeutic targets in cardiac diseases” within the PhD program “Molecular Medicine”.
Moreover, IMTTS scientist Alessia Costa was enrolled in the PhD program “Regenerative Sciences” and has successfully defended her PhD thesis “Establishment of a human reporter cell line for the identification of cardiac regenerative targets”.
New in silico approach for transcription factor regulation screening
Analyzing regulatory elements of hypoxia-sensitive genes in silico predicted the transcription factors SP1 and KLF5 as potential orchestrators in human endothelial hypoxic gene expression. Further studies revealed that these transcription factors also modulate angiogenesis by regulating proliferation and tube formation of endothelial cells. In summary, an intuitive in silico approach to screen for transcription factor regulation, allowing the modeling of significant biological processes including, but not limited to, hypoxia has been developed. Such approach is a valuable tool to support RNA-based therapeutic interventions in transition to clinical stage.
The study was led by IMTTS researcher Arne Schmidt in collaboration with Maximilian Fuchs from the Department of Bioinformatics at the University of Würzburg under the supervision of PD Dr. Jan Fiedler, Prof. Dr. Dr. Thomas Thum and Dr. Meik Kunz. Their work entitled “Deciphering Pro-angiogenic Transcription Factor Profiles in Hypoxic Human Endothelial Cells by Combined Bioinformatics and in vitro Modeling” was published in in the journal “Frontiers in Cardiovascular Research”.
Please find the original article here: https://www.frontiersin.org/articles/10.3389/fcvm.2022.877450/full
Berlin was calling
The 24th World Congress for the International Society for Heart Research (ISHR) took place this year in Berlin in mid-June. More than 650 participants attended with over 125 lectures, three of which, were given by institute director Prof. Dr. Dr. Thomas Thum entitled:
“CircRNAs as new therapeutic targets in HFpEF”,
“MicroRNAs targeting the SARS-CoV-2 entry receptor ACE2 in cardiomyocytes”, and
“ncRNAs-based therapeutic approaches in HF”.
IMTTS researchers: PD Dr. Christian Bär, Sarah Cushman, and Marida Sansonetti were also in attendance with posters in the following sessions:
“Regeneration, Re-engineering & stem cells” and
“Dysfunction, inflammation and contractile proteins.”
DFG grant for investigating senescence in pulmonary and cardiac diseases
IMTTS’s principal investigator PD Dr. Christian Bär and Professor Christina Brandenberger (Institute of Functional Anatomy, Charité Berlin) received a 500,000 € grant for the research project “Targeting telomere dysfunction-related immune- and organ senescence in pulmonary and cardiovascular disease” funded by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) for a period of three years. The project aims to untangle both mechanisms and interactions of the heart-lung axis in acute lung injury and myocardial infarction as well as to study telomere dysfunction-associated related senescence of the immune system, of heart and lungs. Hence, the ultimate goal of these studies will be to improve age-related regeneration and survival in both diseases.
Neonatal injury models to study heart regeneration
Our recent review, published in Basic Research in Cardiology, provides a comprehensive overview of neonatal cardiac injury mouse models, which are widely used for the identification of molecular targets with pro-proliferative potential. These models are essential for understanding and investigating the regenerative potential of mammalian heart. Here we have briefly summarized well-known factors that may stimulate heart regeneration by inducing endogenous cardiomyocyte proliferation in mammals. Further, we highlight the findings emerged in large animal models and in human newborns, which pave the way for promising translational therapies for cardiac regeneration.
Please find the review here: https://link.springer.com/article/10.1007/s00395-022-00931-w
IMTTS Director Professor Thum was awarded a prestigious ERC Advanced Grant by the European Research Council (ERC)
Heart failure is one of the most common causes of death worldwide. In Germany, around four million people suffer from cardiac insufficiency. Besides others, remodeling processes in the heart muscle lead to this disease. These processes, inter alia, can be triggered by side effects of chemotherapy.
So far, there is no treatment option that can stop or even reverse the course of the disease. Professor Dr. Dr. Thomas Thum and his team are now looking for such a strategy within the research project REVERSE.
The focus will be on so-called circular RNAs (circRNA), which belong to the group of non-coding RNAs (ncRNA).
"Within the family of ncRNAs, circRNAs are particularly stable and species-conserved, i.e. largely unchanged in the course of evolution," explains Professor Thum. "This makes them ideal targets for drugs."
As first step, a circRNA library will be screened for suitable candidates which will be challenging as, so far, approximately 20,000 to 30,000 different circRNAs have been identified but only for around ten of those their mode of action has been ascertained. Thereafter, IMTTS researchers want to check whether the selected RNA structures actually control the cardiac remodeling in the case of heart damage caused by chemotherapy or other triggers fostering apoptosis in the heart. For this approach, the scientists will use living myocardial slices.
In the following, it will be investigated how cardiotoxicity can be stopped.
Please find more information about this important topic in the entire article: https://www.mhh.de/en/presse/mhh-insight/startseite-news-detailed-view/mhh-researcher-wants-to-stop-harmful-effect-of-chemotherapy-on-heart-muscle
IMTTS receives 2.5 million euros from the European Innovation Council (EIC) to further develop an anti-fibrotic cardiac RNA drug (FIBREX project)
Professor Dr. Dr. Thomas Thum and IMTTS researchers discovered a specific long non-coding RNA, which is named Meg3 and is crucial for controlling fibrosis formation in heart failure, in the past.
Within the scope of the FIBREX project, the developed Meg3 inhibitor will be further tested in animal models for efficacy safety in order to reach clinical maturity.
For this phase of drug development, it is usually very difficult to get the necessary financial support. However, the new EU innovation funding line closes this gap, now. Thus, Professor Thum and his team are confident that they will further develop their patented Meg3 inhibitor into an effective fibrosis drug that will drastically revolutionize medical practice, reduce healthcare costs and, last but not least, significantly improve patients' lives.
Please find more information about this important topic in the entire article: https://www.mhh.de/en/presse/mhh-insight/startseite-news-detailed-view/mhh-on-the-home-stretch-to-the-rna-drug-against-cardiac-fibrosis
IMTTS researcher Sarah Cushman receives DGK poster prize
Sarah Cushman, a PhD student at IMTTS was awarded the prestigious poster prize from the German Cardiac Society (DGK) at the society’s annual conference in Mannheim for her poster entitled “Insights into the role of circular RNA, circREGEN, in cardiomyocyte proliferation and cardiac regeneration”, which was selected out of hundreds of posters. This poster delves into the role by which circREGEN influences the regenerative potential of the heart, as well as the protective effect it offers against stress inducing factors.
IMTTS is well represented at the DGK’s annual conference
IMTTS director Professor Dr. Dr. Thomas Thum and IMTTS researchers Naisam Abbas, Dr. Dongchao Lu, Sonja Groß, Hannah Hunkler, Arne Schmidt, Dr. Mira Jung, Sarah Cushman, Marida Sansonetti, Alessia Costa, Wen Pan, Dr. Christian Bär, Dr. Shambhabi Chatterjee, Dimyana Neufeld, Dr. Anselm Derda, Kevin Schmidt, Christopher Jahn and Jan Weusthoff attended the 88th annual meeting of the DGK (German Society of Cardiology) in Mannheim and presented their work on molecular therapies (ncRNA, small molecules) of heart failure. The attendance of IMTTS researchers Sonja Groß, Hannah Hunkler, Sarah Cushman, Dimyana Neufeld, Kevin Schmidt, Christopher Jahn and Jan Weusthoff was supported by travel grants from the DGK. Naisam Abbas, Marco Bentele, Elisa Mohr, Sinje Biß, Malte Juchem, Lili Ye and Anabel Lambrecht received travel stipends from the Young DGK Section.
The Best Poster Award goes to Dr. Shambhabi Chatterjee at Dutch-German Joint Meeting
IMTTS researcher Dr. Shambhabi Chatterjee received the best poster award at the 19th Dutch-German Joint Meeting of the Molecular Cardiology Working Groups including a cash prize of 100€. She had presented her poster entitled “Telomerase is essential for differentiation of human iPSCs into cardiomyocytes”. Dr. Chatterjee’s research highlights the importance of the telomerase enzyme for the development and survival of cardiomyocytes since the absence of telomerase and shorter telomere lengths result in poor differentiation efficiency and higher susceptibility to cell death. This research work also established an elegant in vitro model where telomerase activity and telomere lengths can be modulated at will. Hence, this research work also helped to generate a platform with high potential for drug screening and pre-clinical testing for future research investigations.
IMTTS receives funding of 500,000€ from Lower Saxony for Long COVID studies
As around ten to fifteen percent of all SARS-CoV-2 infected people suffer from late effects of COVID‑19, and a mild or asymptomatic infection seemingly does not protect against this, it is of great interest to investigate causes of Long COVID and to develop treatment options. With COFONI (COVID‑19-Forschungsnetzwerk Niedersachsen), the state of Lower Saxony has created a cross-disciplinary research network that aims to combat the long-term consequences of the pandemic.
Within the scope of Lower Saxony‘s COVID-19 research network, the state is providing 5.97 million euros for thirteen interdisciplinary projects. There is special support only for four research projects focusing on Long COVID using special funds, thus, enabling an immediate commencement of the study. One of these research projects will be carried out by IMTTS researchers. The study will investigate the role of circular RNAs as mediators of SARS‑CoV‑2 infections in the cardiovascular system. Initial cell culture experiments have shown that manipulation of certain circular RNAs can potentially inhibit SARS-CoV-2 infection in cardiomyocytes. IMTTS researchers will work together with TWINCORE scientists (Centre for Experimental and Clinical Infection Research) to explore further the therapeutic application of specific circular RNA candidates for COVID-19.
Please find more information on COFONI here: https://www.umg.eu/forschung/corona-forschung/cofoni/
New natural compound similar with anti-fibrotic properties in humans
Activated cardiac fibroblasts – the major cell type of human and murine hearts – contribute to an excessive deposition of extracellular matrix (ECM) leading to cardiac fibrosis and subsequently organ dysfunction. Except the pulmonary drugs, nintedanib and pirfenidone, therapeutics specifically targeting anti-fibrotic pathways are rare.
By screening large libraries of natural occurring compounds, first lead structures lycorine and bufaline with anti-fibrotic properties in vitro and in vivo were previously identified. To improve efficacy of these anti-fibrotic lead structures in vitro validation studies and in silico prediction were combined. Additionally, large OMICs-multi-panel-based mechanistic studies were performed.
Twenty-six similars of the initially identified anti-fibrotic lead molecules bufalin and lycorine were analyzed in human cardiac fibroblasts (HCF) and their anti-proliferative activity and potential toxicity were determined in an array of in vitro and ex vivo studies. Noteworthy, certain similars were more effective at inhibiting HCF proliferation than nintedanib and pirfenidone, even at a lower concentration. Furthermore, low cytotoxicity on human iPS-derived cardiomyocytes and anti-fibrotic gene regulation in human ex vivo living myocardial slices were found for selected similars. Moreover, array and RNA sequencing studies of coding and non-coding RNAs in treated HCFs revealed strong anti-fibrotic properties, especially with the lycorine similar lyco-s (also known as homoharringtonine), that led to a nearly complete shutdown of ECM production at concentrations 100-fold lower than the previously identified anti-fibrotic compound lycorine without inducing cellular toxicity.
In summary, a new natural compound similar with strong anti-fibrotic properties in human cardiac fibroblasts and human living heart tissue was identified which potentially opens new anti-fibrotic treatment strategies.
Please find the publication here: https://doi.org/10.1007/s00395-022-00919-6
IMTTS Director Professor Thomas Thum is a new Member of Lower Saxony’s Life Science-Startup-Board
The Life Science-Startup-Board of Lower Saxony was founded after the first Life Science Startup Day in 2020. At that time, experts of different fields, such as life science and politics, have recognized the great potential of Lower Saxony’s scientific landscape. By founding the Life Science-Startup-Board they laid the foundation for expanding and strengthening the ecosystem of Life Science-Startups in Lower Saxony. Additionally, they aim to improve its attractiveness.
In particular, the first two work priorities are elaborating potential solutions for more transparency, rapidness and startup friendliness especially with regard to IP based spin-offs and working on the initiative RAPID – Response Against Pandemic Infectious Diseases. The latter will allow a greatly accelerated and early development of new and safe drugs and therapeutics against future pandemic infectious diseases.
For these approaches, an interdisciplinary team is necessary. Thus, the Life Science-Startup-Board 2022 is chaired by Dr. Sabine Johannsen, state secretary of Lower Saxony‘s Ministry of Science and Culture, and Stefan Muhle, state secretary of the Ministry of Economics, Labor, Transport and Digitization of Lower Saxony and furthermore, consists of six scientists and founders. One of those is the director of IMTTS and Fraunhofer ITEM as well as founder of Cardior Pharmaceuticals GmbH Professor Dr. Dr. Thomas Thum.
Please find out more about Lower Saxony’s Life Science-Startup Board here: https://startup.nds.de/expertinnengremium-niedersaechsische-life-science-startup/
MicroRNA therapeutics in cardiac ischemia/reperfusion (I/R) injury
RNA therapy is the novel gene therapy for cardiac vascular diseases. IMTTS scientists observed that miR-486 protects against cardiac I/R injury and myocardial apoptosis through targeting PTEN and FoxO1 as well as activation of the AKT/mTOR pathway. Overexpression of miR‑486 might be a promising therapeutic strategy for myocardial protection.
Please find the publication here: https://pubmed.ncbi.nlm.nih.gov/35077859/
Animal models and animal-free innovations for cardiovascular research: current status and routes to be explored.
Consensus document of the European Society of Cardiology (ESC) Working Group on Myocardial Function and the ESC Working Group on Cellular Biology of the Heart
Cardiovascular diseases represent a major cause of morbidity and mortality, necessitating research to improve diagnostics, and to discover as well as test novel preventive and curative therapies. All of which warrant experimental models that recapitulate human disease. The translation of basic science results to clinical practice is a challenging task. In particular, for complex conditions such as cardiovascular diseases, which often result from multiple risk factors and co-morbidities. This consensus document highlights recent advances in trying to reduce the number of animals for cardiovascular research. These models range from stem cell-derived models to in situ modelling of heart properties, bioinformatic models based on large datasets, and improved current animal models, which show clinically relevant characteristics observed in patients with a cardiovascular disease. Hereby, the aim is to provide a guide to help researchers in their experimental design to translate bench findings to clinical routine taking the replacement, reduction and refinement (3R) as a guiding concept.
Please find the new position paper by the ESC here: https://doi.org/10.1093/cvr/cvab370
IMTTS is a Collaborator of the DFG Collaborative Research Center 1470
The German Research Foundation (DFG) provides initial funding of € 12 million for a period of four years for a new Collaborative Research Center (CRC) led by Charité to study the underlying mechanisms of a specific type of heart failure – known as “heart failure with preserved ejection fraction” (HfpEF) – and to develop targeted treatments.
Hannover Medical School is one of the CRC 1470 collaborators. IMTTS will be responsible for the project “Mechanisms, therapeutics and diagnostic potential of circular RNAs in HfpEF”. Within this project, the researchers will focus on three specific, interconnected work packages. The overall goal of these is to investigate how circular RNAs are mechanistically involved in cardiac remodeling and diastolic dysfunction.
“We have established and published relevant methods for cardiac phenotyping, RNA sequencing and analysis,” says Prof. Dr. Dr. Thomas Thum. Furthermore, he clarifies: “Specifically, we aim (1) to improve our understanding about the function and potential therapeutic modulation using in vitro and ex vivo models of HFpEF, (2) to establish a new cell‑type specific circRNA-based therapeutic approach of HFpEF and (3) to test whether selected circulating noncoding RNAs can serve as stratification markers in various cohorts of patients with HFpEF. The ambition and vision of this project is to develop a next generation therapeutic approach for HFpEF patients within the first funding period of the CRC and beyond.”
Please find more information on the official website: DFG Sonderforschungsbereich 1470 - DFG Collaborative Research Centre 1470 (charite.de)
IMTTS director Professor Thum is senior author of the new position paper by the European Society of Cardiology
Targeted therapies in genetic dilated and hypertrophic cardiomyopathies: from molecular mechanisms to therapeutic targets.
The Translational Committee of the Heart Failure Association (HFA), representatively chaired by IMTTS director Professor Dr. Dr. Thomas Thum, and the Working Group of Myocardial Function of the European Society of Cardiology (ESC) organized a workshop to discuss recent advances in molecular and physiological studies of various forms of cardiomyopathies.
Due to several new study setups, such as induced pluripotent stem cells, three-dimensional printing of cells, use of scaffolds and engineered heart tissue, investigating of cardiomyopathies has increased in recent years. In addition, the knowledge on consequences of mutated proteins has deepened, with relevance for cellular homeostasis, protein quality control and toxicity, often specific to particular cardiomyopathies, with precise effects explaining the aberrations.
Therefore, new avenues to treat cardiomyopathies, using contemporary techniques from the molecular toolbox, such as gene editing and repair using CRISPR-Cas9 techniques, antisense therapies, novel designer drugs, and RNA therapies, are available.
Please find the discussion of HFA and the Working Group of Myocardial Function of ESC regarding the connection between biology and diverse clinical presentation, as well as promising new medications and therapeutic avenues, which may be instrumental to come to precision medicine of genetic cardiomyopathies, here: https://onlinelibrary.wiley.com/doi/10.1002/ejhf.2414
Prof. Dr. Dr. Thomas Thum is again one of the Highly Cited Researchers
The company “Clarivate Analytics” analyzed scientific publications from 2010 to 2020 and identified the worlds most cited researchers 2021. These scientists have produced multiple highly cited papers that rank in the top 1% by citations for field and year in the Web of Science™.
IMTTS director Professor Thum is again among these researchers. He is listed in the “Cross-Field” category, which means that these researchers have an impact on various science topics, not only within their actual field of work.
The current list of Highly Cited Researchers (https://hcr.clarivate.com/) contains about 6,600 researchers from 21 disciplines in natural, life and social sciences. Thereof, more than 300 scientists are working in Germany and three – Prof. Dr. Dr. Thomas Thum, Prof. Dr. Michael Manns and Prof. Dr. Thomas Werfel – at the Hannover Medical School.
Research Team studies the promotion of cardiac hypertrophy in mice through the action of lncRNA NRON
Long non-coding RNAs have been shown to have an important role in many different cellular mechanisms, including the regulation of transcription factors. The calcineurin/NFAT-signaling pathway is one of the most important pathways in pathological cardiac hypertrophy. A research group of the Institute of Molecular and Translational Therapeutic Strategies took a closer look at the regulatory mechanisms behind the NFAT-signaling pathway and analyzed NFAT’s regulator, the lncRNA NRON, with regard to its importance for the development of cardiac hypertrophy. Hypertrophic stimuli in neonatal mouse cardiomyocytes led to a downregulation of NRON, while NRON overexpression led to an increase in expression of hypertrophic markers. To study this in more detail, the researchers used a mouse model of transverse aortic constriction (TAC)-induced hypertrophy and performed NRON gain- and loss-of-function experiments. Interestingly, cardiomyocyte-specific NRON deletion attenuated cardiac hypertrophy in mice. Heart weight, cardiomyocyte cell size, hypertrophic marker gene expression, and left ventricular mass showed a NRON-dependent regulation upon TAC‑induced hypertrophy, suggesting a regulatory function of NRON in the heart in vivo. The study, led by the institute’s director Professor Dr. Dr. Thomas Thum and PD Dr. Christian Bär, has been funded by the German Research Foundation and was published in the journal Molecular Therapy. First authors are Dr. Jeannine Hoepfner and Dr. Julia Leonardy.
Please find the publication here: https://pubmed.ncbi.nlm.nih.gov/34856383/
Non-coding RNAs: The key regulators – Find out more about their fascinating roles in cell life and therapeutic perspective in cardiac regeneration
Non-coding RNAs, particularly microRNAs, long non-coding RNAs, and circular RNAs emerged as critical regulators of gene expression that were shown to fine-tune cellular processes both on the transcriptional and the post-transcriptional level. Therefore, they are interesting/potential candidates for cell therapy approaches, in particular in the field of cardiac regeneration.
Please find our review about this crucial topic here: https://doi.org/10.1093/cvr/cvab335
The Hannover Biomedical Research School (HBRS) prize for the best PhD thesis goes to Stevan Stojanović
IMTTS researcher Dr. Stevan Stojanović was awarded with the HBRS prize for the best PhD thesis and his work on drug discovery of anti-senescence therapeutics (Preclinical development of anti-senescence therapeutics for the treatment of lung fibrosis).
IMTTS researcher Dr. Erika Hilbold has been accepted for participation in the interdisciplinary program “Translational Research & Medicine: From Idea to Product” organized by TRAIN (Translational Alliance in Lower Saxony) Academy. The two-year, career-oriented education program will provide her with skills that are essential for translational health research. Different modules will guide her through the individual steps of the translational development aiming to understand the finding, production and clinical application of drug candidates. In addition, transferable and soft skill courses (for example good questioning or presentation techniques) as well as individual personal coaching will be part of the program.
Dr. Erika Hilbold has been accepted for a stipend by „Gesellschaft der Freunde der MHH (GdF) e.V.“, which covers the total costs of the education program.
Hans-Jürgen-Bretschneider awards for IMTTS researchers Sarah Cushman and Sonja Groß
IMTTS researchers Naisam Abbas, Sarah Cushman, Sonja Groß, Arne Schmidt, Kevin Schmidt and Jan Weusthoff presented their work at the autumn meeting of the German Society of Cardiology (DGK) “Herztage 2021” in Bonn.
Due to the Covid-19 pandemic, the conference was a hybrid event and for the first time Hans‑Jürgen-Bretschneider poster awards were converted to abstract prizes.
For their extraordinary abstracts, both, Sarah Cushman and Sonja Groß were honored.
Sarah Cushman received the Hans-Jürgen-Bretschneider abstract award for “Investigating the role of circular RNA, circREGEN, in cardiomyocyte proliferation and cardiac regeneration” in the session “Kardiovaskuläre Reparatur und Regeneration” at the Basic-Science Meeting.
Here is a short summary of her work:
The regenerative potential of the heart is limited after heart failure due to the inadequate proliferative capacity of cardiomyocytes in an adult. A novel circular RNA, circREGEN, is currently under investigation as a potential regulator of cardiac regeneration and cardiomyocyte proliferation. Using in vitro assays in multiple cell types and additionally in ex vivo living myocardial slices, we are able to see promising data showing the up‑regulation of circREGEN in different models of cardiac diseases as well as a decrease in proliferation after circREGEN levels are reduced. These initial findings allow us to further investigate the promising potential of circREGEN for future translational therapy.
Sonja Groß was able to show that “Inhibition of TGFβ1-induced long non-coding RNAs prevents cardiac fibrosis”. She was awarded with the Hans-Jürgen-Bretschneider abstract prize in the session “Transkriptomregulation bei Herzerkrankungen” at the Basic-Science Meeting.
Please find out more about her work here:
Aiming at the discovery of new therapeutic strategies for the treatment of cardiac fibrosis, two novel long non-coding RNAs (lncRNAs) have been identified. Therapeutic inhibition of the two pro-fibrotic lncRNAs resulted in an impaired in vitro proliferation and migration as well as matrix remodeling that was further assessed in ex vivo living human myocardial slices. These findings underpin the great potential of non-coding RNAs resembling the major focus of our institute's investigations.
IMTTS spin-off Cardior raises €64 million
IMTTS spin-off Cardior Pharmaceuticals GmbH receives €64 million from an international syndicate of investors for clinical translation of selected non-coding RNA therapeutics.
MicroRNA therapeutics – the next generation of heart failure medication
A novel porcine model of non-ischemic cardiac hypertrophy and fibrosis was established and the effect of inhibition of micro-ribonucleic acid 132 (miR-132) on heart failure development was investigated in these pigs.
Therefore, a percutaneous reduction stent was implanted in the thoracic aorta inducing progressive remodeling at day 56 after pressure-overload induction. To determine the effect of inhibiting miR-132, antimiR-132 (an antisense oligonucleotide specifically inhibiting miR-132) was regionally applied via intracoronary injection at day 0 (percutaneous transverse aortic constriction induction) and day 28.
The intracoronary injection of an antimiR-132 reduced cardiomyocyte cross-sectional area, retarded fibrosis and improved capillary density as well as left ventricular ejection fraction in the pigs.
In conclusion, inhibiting miR-132 is a valid strategy to prevent heart failure progression in hypertrophic heart disease and may be developed as a treatment for heart failure of non-ischemic origin.
Please find the publication here: https://pubmed.ncbi.nlm.nih.gov/34112319/
IMTTS researcher Dr. Shambhabi Chatterjee received a 50,000 € grant for a COVID‑19 related research project “Exploration and exploitation of non-coding RNAs to prevent SARS-CoV-2 infection in cardiomyocytes” funded by the German Society of Cardiology-Cardiovascular Research e.V. (DGK) for a period of one year. The project aims to identify novel non-coding RNAs, which can regulate SARS-CoV-2 infection in human cardiomyocytes.
Prof. Dr. Dr. Thomas Thum receives Paul-Martini-Award
Prof. Dr. Dr. Thomas Thum, Director of the Institute of Molecular and Translational Therapeutic Strategies, received the Paul-Martini-Award for his research on more effective treatment of heart failure. The Paul-Martini-Foundation is thereby appreciating his outstanding achievements in clinical-therapeutic drug research. Together with his team Prof. Thum developed the antisense RNA drug CDR132L which modulates gene regulation in cardiomyocytes aiming to counteract cardiac remodeling processes in heart failure patients. After a phase I clinical trial was successfully completed in 2020, another study is planned including more patients.
For further information please visit https://www.paul-martini-stiftung.de/paul-martini-preis/2021
IMTTS researcher Mira Jung, PhD, received a 470,000 € grant for the research project “The molecular role of selected circRNAs in cardiac macrophage dynamics and inflammatory response during cardiac remodeling after myocardial infarction” funded by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) for a period of three years. The project aims to exploit circRNA modulation as a tool for macrophage reprogramming towards an anti-inflammatory phenotype, which lead to optimal healing procedure following MI.
IMTTS researcher Dr. Jeannine Hoepfner received a 470,000 € grant for the research project “Deciphering the role of miRNAs in Fabry disease pathology and therapy” funded by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) for a period of three years. The project aims to establish in vitro Fabry disease models based on pluripotent stem cells and to identify therapeutic miRNA candidates.
IMTTS researchers Malte Juchem, Sarah Cushman and Christopher Jahn each won the prize for the best project presentations of the 1st, 2nd and 3rd year “Molecular Medicine” PhD students, respectively, during the annual retreat of the Hannover Biomedical Research School (HBRS).
IMTTS researcher Stevan Stojanović was awarded a prize for his poster on “Modeling And In Silico Reconstruction Of The MiR-506-Quaking Axis In Lung Fibrosis“ at the 'Fraunhofer ITEM Models of Lung Disease 2021 – special edition "Corona"' conference!
SARS-CoV-2 attacks the heart
MHH research team detects biomarkers of cardiovascular burden in blood of COVID-19-affected individuals.
Infections with the SARS-CoV-2 coronavirus do not only mean a burden for the lungs. The virus also massively affects the cardiovascular system. A research group at the Institute of Molecular and Translational Therapeutic Strategies at Hannover Medical School (MHH) has now detected certain biomarkers in severely ill COVID-19 patients that are typically found in inflammatory processes and in patients with heart disease and offer potential new therapeutic targets. The study, led by institute director Professor Dr. Dr. Thomas Thum and Dr. Christian Bär, has been funded by the German Heart Foundation (Deutsche Herzstiftung) and published in the European Journal of Heart Failure. First authors are Ankita Garg, PhD, Dr. Benjamin Seeliger, and Dr. Anselm Derda.
MicroRNAs found to be markers of cardiovascular damage
"We hypothesized that so-called non-coding microRNAs, which do not carry blueprints for genetic information, play an essential regulatory role in the exuberant immune response and subsequent remodeling of connective tissues of the lung and heart. We already knew that these microRNAs are also detectable in blood," explains Professor Thum. In collaboration with the MHH Clinics of Cardiology and Angiology and of Pneumology, the research team examined blood samples from 38 COVID-19 patients who were receiving intensive care and ventilation. "To do this, we focused on various sensitive microRNA markers for cardiovascular damage and analyzed how high their concentration was in the blood serum," says the institute director.
For comparison, the study also examined the blood of influenza patients with Acute Respiratory Distress Syndrome (ARDS), who also required intensive care and ventilation, as well as blood samples from a healthy control group. The result: Compared to the healthy subjects, the concentration of microRNA markers in the blood serum of the critically ill COVID-19 patients was considerably increased. However, it was also significantly different from the values of the critically ill influenza ARDS patients who were also mechanically ventilated.
Evidence that the heart is also affected by SARS-CoV-2 infections may have implications for the treatment of patients. "In our estimation, the heart function of COVID-19 patients would need to be monitored in a long-term course," says the cardiologist Thum. In addition, the research team now wants to investigate whether the biomarkers can also be used to estimate prognosis for disease progression and recovery. The microRNAs could also provide new therapeutic approaches.
Please find the publication here: https://pubmed.ncbi.nlm.nih.gov/33421274/
Gene treatment protects against heart damage caused by chemotherapy
MHH research team uses telomerase for oxygen detoxification in heart muscle cells
According to an estimate by the Robert Koch Institute, around 510,000 people in Germany were newly diagnosed with cancer last year. Due to improved therapies, cancer can be treated more and more successfully - but what causes lasting damage to the tumors often also has severe side effects. The highly effective therapeutic agents from the anthracycline group, for example, prevent cancer cells from dividing. At the same time, however, they promote the formation of free oxygen radicals. These molecules, also known as reactive oxygen species (ROS), are toxic to cells and damage the heart muscle.
This also applies to the drug doxorubicin, which successfully treats cancer cells, but at the same time can cause the death of heart muscle cells (cardiomyocytes). Possible consequences are chronic cardiac insufficiency or even heart failure. So far, there are hardly any therapeutic approaches against cardiotoxicity of chemotherapy. A research group from the Institute of Molecular and Translational Therapeutic Strategies at Hannover Medical School (MHH) has now found an approach to save cardiac function. The study, led by institute director Professor Dr. Dr. Thomas Thum and Dr. Christian Bär, has been funded by the German Research Foundation and published in the journal Molecular Therapy. First author is Dr. Shambhabi Chatterjee.
"Immortality enzyme" frees cells from toxic oxygen compounds
The research group has focused on telomerase. The enzyme protects the ends of the chromosomes, the telomeres, from damage and shortening during cell division. In this way, the cell retains its ability to divide and does not age. This is why telomerase is also known as the "immortality enzyme" and is the subject of anti-aging research. "In adults, this enzyme is normally switched off," explains Dr. Bär. Only in certain cell types, such as blood stem cells, telomerase is still active. In previous studies in mice, the molecular biologist had already found that switching on telomerase helps against age-related diseases and protects the heart. Because cardiomyocytes do not divide in adult mammals, the research team suspected that telomerase clears the cells from toxic oxygen radicals by performing an "extra-telomeric task" beyond its function. They used doxorubicin to initially increase ROS levels and induce cardiotoxic effects. In the mouse model, the administration of telomerase via a gene shuttle resulted in detoxification of cardiomyocytes, better protection from cell death, and thus improved cardiac function. This protective effect was confirmed in experiments with human cardiomyocytes derived from induced pluripotent stem cells.
Telomerase also protects the "power plants" of the cells
"Gene therapy with telomerase apparently prevents cell death in cardiomyocytes," says Dr. Bär. At the same time, it also protects the mitochondria from the harmful side effects caused by the chemotherapeutic drug. Mitochondria, as the "power plants of the cell," provide the necessary energy for all metabolic processes and are also sensitive to doxorubicin-promoted ROS formation. "When the cell is under stress, telomerase migrates from the nucleus to the mitochondria and protects them from damage," the researcher explains. In cardiomyocytes, detoxification of the cellular “power plants” ensures that the heart's pumping function improves. Telomerase gene therapy could be a new strategy to prevent heart damage caused by chemotherapeutic agents.
Please find the publication here: https://pubmed.ncbi.nlm.nih.gov/33388418/
MHH Professor Thum starts as institute director at Fraunhofer ITEM
The cardiologist and bioscientist expands ITEM's focus on cardiac research.
Professor Thomas Thum is the new director of the Fraunhofer Institute for Toxicology and Experimental Medicine ITEM in Hannover since January 1, 2021. From now on, he is heading the Institute together with Professor Krug. In addition, Professor Thum has accepted the call to the W3 professorship "Translational Validation of Innovative Therapeutics" at the neighboring Hannover Medical School (MHH), which comes with the Fraunhofer Institute directorship.
For many years, the cardiologist and bioscientist has been conducting research in the field of functional characterization and translational potential of RNA molecules for new therapies against cardiovascular diseases, most recently at MHH as professor and director of the Institute of Molecular and Translational Therapeutic Strategies. With more than 400 publications, he is a world-renowned expert in this field. Currently, Professor Thum is conducting research on the diagnosis and therapy of organ dysfunction and fibrosis, gene therapy approaches as well as mechanisms of COVID-19 disease and corresponding therapeutic strategies with regard to the cardiovascular system and beyond. As a spin-off of MHH, he founded the successful biotech company Cardior Pharmaceuticals GmbH and holds numerous patents and licenses in the field of RNA diagnostics and therapy.
Expanded focus: heart complements lung
With his research focus, the scientist profitably complements Fraunhofer ITEM's previous focus on lung and respiratory research. In addition to chronic lung diseases, heart failure in particular plays an important role as a globally increasing disease with a prevalence of currently up to 60 million patients and is one of the main reasons for hospitalizations. In particular, due to the COVID-19 pandemic and the long-term effects of the disease, the number of heart failure patients is expected to increase significantly. Despite the growing importance of this disease, little progress has been made in the field of heart failure research over the past 20 years.
"We pursue a completely new approach," says Professor Thum. "Using high-throughput methods and platform technologies, we are looking for RNA-based strategies as an effective therapy for heart failure. We already made remarkable progress in this area and interest from industry is high. The expansion to focus on the organ system heart is both a challenge and a great opportunity for Fraunhofer ITEM. In previous joint projects, we have already been able to identify promising synergies and potentials. I am very pleased to now expand these together!"
Benefit for transfer
While Professor Thum's work in the context of his new MHH professorship will be primarily basic research-oriented, his Fraunhofer activities will be more translational and application-oriented, in line with the Fraunhofer model. "We are delighted that with Professor Thum, an outstanding researcher will further expand and strengthen the synergies between MHH and Fraunhofer ITEM," says MHH President Professor Dr. Michael Manns. Fraunhofer's innovative strength in health research will benefit from this once again deepened connection to the Medical School and the intensification of the transfer from basic research to application, ultimately benefiting people. Professor Thum has already been able to bring several molecules identified in the laboratory into clinical application in humans.
"Not only scientific success, but also transfer competence is a key success criterion for a Fraunhofer institute. For this reason, I am extremely pleased to shape the future of Fraunhofer ITEM together with Professor Thum, to provide decisive scientific impulse and to bring it to application," emphasizes Professor Krug. "The further development of the institute is an important step in realizing our vision - to be a pioneer for sustainable health."
Both institute directors will lead Fraunhofer ITEM in tandem. Professor Thums' area of responsibility will cover Preclinical Pharmacology and Toxicology, Chemical Safety, and Translational Medical Engineering. He will also establish a new research unit "Cardiovascular Research" at the institute. Professor Krug will continue to be responsible for Clinical Respiratory Research, Pharmaceutical Biotechnology at the Braunschweig site and Personalized Tumor Therapy at the Regensburg site.
IMTTS researcher Dr. Ankita Garg was awarded with the HBRS prize for her PhD thesis „Regulation, Diagnostics and Therapy focusing on the Mineralocorticoid Receptor involved in Cardiac Remodeling“.
Helpers against COVID-19 infection?
microRNAs block the gateway for SARS-CoV-2 in heart muscle cell cultures
Infections with bacteria and viruses are an additional burden for the cardiovascular system. This also applies to the coronavirus SARS-CoV-2. But the virus seems to lead to heart damage not only in older people with underlying cardiovascular diseases. Also only slightly ill, younger patients can have inflammatory changes in the heart muscle or in the pericardium after a COVID-19 infection.
The reason for this is the angiotensin-converting enzyme 2 (ACE2). This binding site is the gateway for SARS-CoV-2 in the lung tissue. Because ACE2 is also present in heart muscle cells, the viruses can also infect the heart and trigger massive inflammations. A research group of the Institute for Molecular and Translational Therapeutic Strategies has now discovered a way to block this way for the corona virus. The study under the direction of the institute director Professor Dr. Dr. Thomas Thum and Dr. Christian Bär was published in the "Journal of Molecular and Cellular Cardiology".
ACE2 controls salt and fluid content in the body and regulates the blood pressure. As a docking station for coronaviruses the enzyme also plays a central role in COVID-19. “As one of the main receptors for SARS-CoV-2, ACE2 is simultaneously a potential target for combating COVID-19," explains Professor Thum.
His team has been looking for possibilities, to reduce the enzyme concentration and, by using bioinformatics approaches, discovered a group of microRNAs which control the process. MicroRNAs are tiny, non-coding RNAs that do not translate into the genetic blueprint, but can rather prevent the construction of individual proteins in the cell very specifically. "Especially one candidate, called miR-200c, was able to clearly downregulate the ACE2 activity in heart muscle cells of rats and from human cardiomyocytes produced from stem cells in the laboratory," says Dr. Bär.
In the next step, the results from the cell culture experiments now need to be validated in living organisms. If the study is also successful in a mouse model the use of the miR-200c could be a future strategy in the fight against coronaviruses - even if a vaccine is available. "Also the pathogens of the severe respiratory diseases SARS and MERS belong to the coronaviruses, which enter the cells via ACE2", says Professor Thum.
Please find the publication here: https://pubmed.ncbi.nlm.nih.gov/32891636/
Professor Dr. Dr. Thomas Thum, director of the Institute for Molecular and Translational Therapeutic Strategies, was elected to the Executive Board of the Heart Failure Association of the European Society of Cardiology for a period of two years.
IMTTS researcher Dr. Jeannine Hoepfner was awarded with a research fellowship by the German Society of Cardiology - Cardiovascular Research e.V. (DGK). The DGK is funding her research on "Living myocardial slices for modeling Fabry disease ex vivo" with 50,000 € for one year.
Long non-coding RNA Cyrano in pluripotent stem cells
IMTTS researchers investigated the role of lncRNA Cyrano in stem cell pluripotency / Publication in the journal “Stem Cell Reports”
Pluripotency is tightly regulated and crucial for the self-renewal and differentiation capacity of stem cells. Long non-coding RNAs (lncRNA) are regulators of versatile cellular processes, among them pluripotency. The highly conserved lncRNA Cyrano was previously shown to be essential for the maintenance of pluripotency in murine embryonic stem cells (ESCs) in loss-of-studies with shRNA. In contrast, we found that Cyrano is dispensable for pluripotency in different genetic models of murine and human induced pluripotent stem cells (iPSC) and ESCs. The modulation of Cyrano by a clean CRISPR/Cas9 knockout, CRISPRi- or siRNA-mediated knockdown had neither an effect on the expression of pluripotency markers, nor the differentiation capacity to the three germ layers. The whole transcriptome revealed only mild changes by the Cyrano knockdown. Hannah Hunkler, first-author of this work says: “This study underlines the importance of using different approaches and different in vitro systems when investigating the phenotypic consequences of gene inactivation.”
Please find the publication here: https://pubmed.ncbi.nlm.nih.gov/32531193/
IMTTS researchers successfully apply a novel machine learning approach to improve cardiovascular risk prediction
The aim was to test whether novel biomarkers, such as microribonucleic acids (miRNAs), and nonstandard predictive models, such as decision tree learning, provide useful information for medical decision-making in patients on hemodialysis. In total 810 samples from patients with end-stage renal disease receiving hemodialysis included in the AURORA clinical trial were investigated and specific circulating miRNAs were analyzed. Importantly, Regression tree models identified eight patient subgroups with specific cardiovascular risk patterns.
This work highlights that circulating miRNA profiles can complement conventional risk factors to identify specific cardiovascular risk patterns among patients receiving maintenance hemodialysis. The work was published in Theranostics (Theranostics 2020; 10(19):8665-8676. doi:10.7150/thno.46123).
Please find the publication here:
New approach for gene therapy against cardiac insufficiency
MHH research team publishes study in the European Heart Journal
The most frequent trigger for pathological heart muscle growth, also known as cardiac hypertrophy, is high blood pressure, which makes it harder for the heart to open the aortic valve and to pump blood into the body. To compensate for this, the heart muscle thickens, but at the same time becomes increasingly inelastic, and the pumping capacity is decreasing. As a result, the body is no longer supplied with sufficient oxygen. So far, therapies have only been able to relieve the weakened heart and alleviate symptoms such as shortness of breath or chronic fatigue. Now, researchers from the Institute of Molecular and Translational Therapeutic Strategies at the Hannover Medical School (MHH) discovered a way to reverse the course of the disease. The study under the direction of Professor Dr. Dr. Thomas Thum, director of the institute, and group leader Dr. Christian Bär was published in the renowned journal European Heart Journal. First authors are Dr. Janika Viereck and Anne Bührke.
Biomolecule H19 is the key to improved heart function
The key to therapy is a so-called long non-coding RNA (lncRNA) called H19. It regulates certain growth and developmental processes in the body. In their study the scientists observed that H19 is apparently lost in weakened hearts - in mice and pigs as well as in humans suffering from various heart diseases. "Through a targeted gene therapy with H19, we were able to compensate for this deficiency in the mouse model, to clearly improve the heart function and even partially reverse the course of the disease," explains Janika Viereck.
The research team used a modified viral vector for the therapy, which acts as a gene shuttle transporting the genetic information for H19 selectively into the heart muscle cells, where the blueprint for the lncRNA is directly translated. The special: H19 has hardly changed in its structure during evolution. Not only did the mouse-specific H19 gene have a therapeutic effect in the mice. Similar effects could also be achieved by the administration of the human H19 gene. "Therefore, we hope that our method will work well in humans ", says study leader Bär. The results serve as an important basis for a possible further clinical development of the gene therapy. The study was supported by the German Research Foundation within the framework of the Clinical Research Group KFO311, which is working at the MHH on treatment strategies and regenerative therapies for severe heart and lung diseases.
Please find the publication here:
Prof. Dr. Dr. Thomas Thum and Dr. Anselm Derda received a 50.000 € grant for the research project "Non-coding RNAs as diagnostic and prognostic biomarkers in Covid-19 patients suffering from heart disease" within the COVID-19 project funding of the Deutsche Herzstiftung e.V. (www.herzstiftung.de).
The researchers assume that ncRNAs have an essential regulatory function in the excessive immune reaction in Covid-19 and the subsequent fibrotic remodeling, both pulmonary as well as in the cardiovascular organ system. By using special test methods, it will be investigated which of the ncRNAs show an excessive occurrence in SARS-CoV-2 infected persons. For this purpose, blood obtained from infected persons and from control subjects will be examined. Subsequently, the defective regulation of ncRNA is correlated with the organ dysfunctions of the patients. The researchers anticipate finding a blood-based biomarker that will make it possible to better predict the course of the disease and the prognosis of SARS-CoV-2 infected patients.
04 May 2020
Standardization of echocardiography in experimental rodents
Cardiac function is routinely assessed by echocardiography in both humans and experimental animals. Advanced echocardiographic equipment allows sophisticated monitoring of genetically modified or pharmacologically treated animals. The Working Group on Myocardial Function of the European Society of Cardiology, chaired by the IMTTS director Prof. Dr. Dr. Thomas Thum, recently published a position paper describing standardized procedures - from preparation of the animal over echocardiographic techniques to data analysis - for an accurate and reproducible quantification of left ventricular function in healthy and pathological conditions.
Please find the publication here: https://pubmed.ncbi.nlm.nih.gov/32365197/
COVID-19 research at IMTTS
Cardiovascular disease (CVD) is considered a high risk factor for COVID-19 susceptibility and even mortality. IMTTS researchers put special emphasis in summarizing and critically reflecting molecular insights into the viral infection mechanism aiming to identify potential causes of SARS-CoV-2 infection-related cardiac consequences. These findings might be implicated into optimized therapeutic strategies for the treatment of SARS-CoV-2-infected cardiovascular patients.
Please find the publications here:
18 April 2020
microRNAs as regulators of Aldosterone-Mineralocorticoid Receptor Pathway
MHH researchers identified miRNAs regulating Aldosterone-Mineralocorticoid Receptor Pathway mediated cardiac remodeling / Publication in the journal “European Journal of Heart Failure”
Aldo-MR pathway, which is important to maintain the blood pressure in the body, at times becomes associated with the pathogenesis of various cardiac diseases under abnormal conditions. As a therapy, MR antagonists are widely used in addition to the standard care towards cardiovascular diseases but mechanistic understanding behind this pathway was still lacking. Prof. Dr. Dr. Thomas Thum, director of the Institute of Molecular and Translational Therapeutic Strategies (IMTTS), and his team identified miRNAs as novel regulators of Aldo-MR pathway filling-in these knowledge gaps.
After performing a high-throughput miRNA screen, the team came across microRNA-181a (miR-181a) as a potential regulator of Aldo-MR pathway. Using special animal models for myocardial infarction, the team performed gain and loss-of-function studies for miR-181a, where miR-181a emerged as cardio-protective miRNA specifically deregulating Aldo-MR pathway. As a deeper insight into the modus operandi, Angptl4, an Aldo-MR pathway associated target of miR-181a, was also identified through which miR-181a regulated the pathological phenotype of this pathway.
With this publication, we not only provide a better mechanistic understanding of the pathway but also a novel therapeutic target against deleterious Aldo-MR pathway mediated cardiac remodeling.
Please find the publication here: https://pubmed.ncbi.nlm.nih.gov/32304626/
03 February 2020
Novel therapeutic approach for reversal of heart failure
MHH researcher develop blocking compound against main regulatory switch of heart failure / Publication in the journal “Nature Communications”
In case of cardiac insufficiency or heart failure the heart is unable to pump a sufficient amount of blood through the body. This may result in non-sufficient supply of organs, muscles and other tissues with oxygen and nutrients. So far this disorder is, amongst others, treated with drugs that decrease blood pressure and aims to relieve the heart. Prof. Dr. Dr. Thomas Thum, director of the Institute of Molecular and Translational Therapeutic Strategies (IMTTS) at Hannover Medical School (MHH), follows a novel approach. Together with his team he found a way to switch off the element in the human genome that regulates the pathological growth of the heart muscle at the beginning of heart failure. The research results were now published in the well-respected journal “Nature Communications”.
While searching for so-called non-coding RNAs that regulate specific processes in the cells, the team came across the microRNA-132 (MiR-132). “It acts like a main regulatory switch and is more prevalent in animals and humans with different heart diseases as compared to healthy individuals”, explains Prof. Thum. To shut off MiR-132 the team at IMTTS developed a specific substance. The AntimiR-132 compound as a so-called antisense oligonucleotide is assembled as a mirror image of MiR-132 and captures the pathologically increased presence of the microRNA. “In our studies in a large animal model we could show that use of AntimiR-132 can reduce the miR-132 level in cardiomyocytes and reverse severe heart failure” says Prof. Thum.
The AntimiR-132 was developed under the name CDR at Cardior Pharmaceuticals, a biopharmaceutical company and spin-off of the MHH that is specialized on the development of innovative cardiac therapeutics. “Based on the data of our publication we already tested our lead substance CDR in patients with heart failure” says the cardiologist. In the patients it is tested whether only few administrations of the substance show therapeutic effects without observing side effects. Further clinical studies should follow to further investigate efficacy and safety of the compound. In five years, Prof. Thum hopes, the next generation therapy might receive market approval. Permanent swallowing of tablets might be a thing of the past then. “One infusion per month might probably be sufficient for an effective treatment”, estimates the medical scientist.
Please find the publication here: https://www.ncbi.nlm.nih.gov/pubmed/32005803
22 January 2020
Natural compounds against fibrosis and diastolic heart failure discovered
MHH researcher identified novel therapeutically active compounds / Publication in journal “Circulation”
Nature is an inexhaustible source of therapeutically active compounds. However, searching for a suitable agent against a certain disease often resembles the proverbial search for a needle in a haystack. Now, an international research team from USA, France, Spain, Italy and Germany succeeded to discover even two compounds that inhibit the pathological growth of the heart muscle, known as fibrosis, and at the same time provide relaxation of the heart in the so-called diastolic pumping phase for re-filling the heart with blood. The study was conducted by the Institute of Molecular and Translational Therapeutic Strategies at Hannover Medical School (MHH), directed by Prof. Dr. Dr. Thomas Thum; besides, the well-respected US research institutions Stanford University and Harvard Medical School Boston participated to the research project. Results have now been published by the journal “Circulation”.
Compounds could be basis for novel heart medications
Cardiovascular disease is the world’s number one cause of death – even before cancer. Novel therapies for cardiac insufficiency and accompanied pathological growth of the heart muscle are therefore urgently needed. “In our studies we discovered two promising compounds that can be found in nature and could serve as novel heart medications” says Prof. Thum. In the context of the multidisciplinary EU funding project FIBROTARGETS for the identification of novel therapeutic approaches against fibrosis the researchers investigated 480 out of 150,000 natural compounds from a natural compound library in detail. Two compounds displayed the potential to inhibit the connective tissue cells (fibroblasts) of the pathological weakened heart to promote fibrosis and thereby stiffen the heart. One of the antifibrosis compounds is called lycorin and is a plant-based active agent from Amaryllidaceae species. The second fibrosis inhibitor is called bufalin, originally originates from the toxin of the Chinese toad venom and influences the heart function.
“There is currently no treatment for a diastolic impairment of the heart available”
“We tested both anti-fibrotic compounds first in human fibroblasts and then in mice and rats” explains the cardiologist. Due to the natural compounds we succeeded to prevent fibrosis in the heart and to improve the diastolic function of the heart in both animal models. Thereby, a therapeutically active dose of the compounds is obviously well tolerated and, according to first toxicological analyses, neither harmful to liver nor to kidneys. “The sensational thing about it is that there are currently no therapies for a diastolic impairment of the heart available” underlines the researcher. This means great hope for more than 30 million patients worldwide suffering from heart failure and diastolic cardiac insufficiency at the same time. The international research team assumes that the publication will raise great response from the scientific community.
Please find the publication here: https://www.ncbi.nlm.nih.gov/pubmed/31948273
17 January 2020
MHH researcher wants to develop novel drug against cardiac fibrosis
Prof. Dr. Dr. Thomas Thum receives well-respected funding award for frontier research of the European Union
For his research on a novel drug against cardiac fibrosis Prof. Dr. Dr. Thomas Thum, director of the Institute of Molecular and Translational Therapeutic Strategies, already received one of the most important funding for excellent research of the European Union. His research project LONGHEART was awarded with the well-respected ERC Consolidator Grant of the European Research Council (ERC). Now, the EU again supports the medical scientist with the ERC Proof of Concept Grant and EUR 150,000 funding for his new project MEGFIB. The aim of this project is to follow up on the results obtained from his frontier research of the current LONGHEART project and to launch a drug against fibrosis.
Workload of the heart is increasing extensively
Cardiac fibrosis is a hallmark of heart failure. The heart that is weakened by myocardial infarction or high blood pressure, tries to compensate its reduced ability to pump blood by increasing its own volume: the heart is growing more and more, thereby overloading itself. Connective tissue cells (fibroblasts) are often proliferating in the heart muscle, which leads to increased stiffness of the heart.
Specific therapies against cardiac fibrosis are still missing
Specific treatment against this cardiac fibrosis is missing. For a potential therapy, Prof. Thum and his team rely on so-called long non-coding RNAs (lncRNAs). These are parts of our genome that are not responsible for protein production but for regulation of distinct processes in the cells. “During the LONGHEART project we identified a novel, innovative target molecule lncRNA-Meg3 which regulates fibrosis in heart failure”, explains Prof. Thum. The researchers already investigated this in mice and generated a so-called antisense oligonucleotide which inhibits the fibrosis-regulating RNA.
First achievements in animal experiment
The result: By shutting down the Meg3 structure the fibrosis propensity is reduced. At the same time, the diastolic function of the heart - that means relaxation of the muscle – is improved. This function of the heart is strongly impaired in almost half of all patients suffering from heart failure. Since the Meg3 structure in connective tissue cells of the heart (fibroblasts) is very similar in mouse and human, these observations are most likely also translatable to human models.
Results translatable to human tissues?
In the context of MEGFIB the research team aims to translate the efficacy of the Meg3 inhibitor to human cells and tissues. Therefore, human cardiac fibroblast-based cell culture systems will be established. Moreover, strategies for production and marketing of the Meg3 inhibitor as a fibrosis drug will be developed. Cooperation partner of the IMTTS is Cardior Pharmaceuticals which is a biopharmaceutical spin-off of the MHH and is specialized on the development of non-coding RNA-based drugs for the treatment of heart failure.
11 – 15 November 2019
EATRIS, the European infrastructure for translational medicine, is a European consortium connecting academic centres across Europe with the aim to improve academic translational output. As this is only possible with continuous teaching and training, this year EATRIS brought together their experience of their C-COMEND and ENLIGHT-TEN courses on translational research and medicine development to establish the TMex (Translational Medicine Explained) Winter School.
The highly interactive 5-day face-to-face workshop in Barcelona, Spain, was designed around the translational pipeline with a focus on de-risking projects as well as broadening the perspective from preclinical research to preparing successful market entries. During the course IMTTS researcher Fabian P. Kreutzer advertised his research with a talk, presented the broad picture during the poster session, led his team to victory of the “test tubes to tablets” board game and successfully communicated a company’s position during a simulated TV interview.
10 -12 October 2019
IMTTS researchers Dr. Christian Bär, Anna Meinecke and Fabian P. Kreutzer visited the annual Herztage conference of the German Cardiac Society (DGK) in Berlin. Besides detailed discussions on the latest heart failure trials communicated during the summer, Anna Meinecke and Fabian Kreutzer presented their latest work in the basic science poster sessions.
Congratulations for Prof. Thomas Thum reaching the 10 year jubilee at Hannover Medical School!
The Clinical Research Group KFO311 was positively evaluated by the DFG and will be funded for another 3 years
The clinical Research Group KFO311 on “Advanced cardiac and pulmonary failure: mechanical unloading and repair” will be funded for a second 3-years funding period. The consortium brings together outstanding scientific and clinical expertise of the participating MHH Departments and Institutes. The overarching aim is to explore the effects of mechanical unloading on local and systemic pathomechanisms in advanced cardiac and pulmonary failure and to improve current and/or develop novel therapeutic strategies. Early translational approach will be evaluated in preclinical and clinical trials. Within the first funding period the IMTTS successfully investigated the long non-coding RNA H19 during unloading and repair of dysfunctional myocardial tissue in mice. In close collaboration with PD Dr. S. Cebotari (Co-PI together with Prof. Thum in KFO311 Project 9) a pig model for cardiac unloading was developed as an valuable large animal model towards clinical translation. Based on our findings in a cardiac hypertrophy mouse model, this pig model will be employed in the second funding period to test inhibition of the long non-coding RNA Meg3 as anti-fibrotic treatment during cardiac hypertrophy and unloading. The DFG funds our subproject with EUR 444,600.
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Das Institut für Molekulare und Translationale Therapiestrategien (IMTTS) an der Medizinischen Hochschule Hannover (MHH), das sich derzeit auf die Identifikation funktionaler, langer, nicht-kodierender RNAs (lncRNAs) konzentriert, die eine wichtige Rolle bei der Regeneration und Alterung des Herzens spielen, gab heute den Erhalt von Fördermitteln in Höhe von EUR 300.000 für ein gemeinsames Forschungsprojekt mit Cardior Pharmaceuticals GmbH bekannt. Das Projekt hat das Ziel, therapeutische Oligonukleotide zur Behandlung von Herzerkrankungen zu identifizieren und präklinisch zu entwickeln. Die Fördermittel werden vom Land Niedersachsen und dem Europäischen Fonds für Regionale Entwicklung (EFRE) bereitgestellt. Die für drei Jahre geplante Kooperation wird 2019 beginnen.
„Wir wollen Herzinsuffizienz aufhalten und kurieren, indem wir regulatorische Ribonukleinsäuren (RNAs) blockieren, die eine entscheidende Rolle bei der Entwicklung dieser facettenreichen Krankheit spielen”, sagte Prof. Dr. Dr. Thomas Thum, Direktor des IMTTS und Forschungsvorstand von Cardior. „Unser erster Produktkandidat CDR, ein synthetisches Antisense-Oligonukleotid, blockiert eine microRNA, die als molekularer Hauptschalter an der Entstehung von Herzinsuffizienz nach einem Herzinfarkt beteiligt ist. Dieser Ansatz kann auch auf andere RNA-Targets und weitere Herzerkrankungen angewendet werden. Ziel dieser Kooperation ist die Identifikation von neuen Targets und therapeutischen Oligonukleotiden, die unsere Wirkstoffpipeline zur Bekämpfung von Herzerkrankungen erweitern.”
Der Kooperationspartner des IMTTS, die Cardior Pharmaceuticals GmbH, ist ein Unternehmen, das sich auf die Entwicklung von Therapeutika aus nicht-kodierender RNA (ncRNA) für Patienten mit Herzinfarkt und Herzinsuffizienz konzentriert. Im Rahmen der Kooperation will Cardior sein Portfolio an Wirkstoffkandidaten zur Behandlung verschiedener Indikationen im Bereich Herzinsuffizienz verbreitern.
The Institute of Molecular and Translational Therapeutic Strategies (IMTTS), directed by Prof. Dr. Dr. Thomas Thum, has joined the COST Action CA17129 „Catalysing transcriptomics research in cardiovascular disease (CardioRNA)“. Prof. Thum has been nominated as Substitute Member of the Management Committee on behalf of Germany. COST (European Cooperation in Science and Technology) actions are a European instrument to support cross-linking of national research activities on the European level. COST actions do not support individual research projects but rather networking activities, like congresses and exchange of scientists. The main aim and objective of the COST Action CardioRNA is to accelerate the understanding of transcriptomics in cardiovascular disease and further the translation of experimental data into practical applications for diagnostics and therapies. The COST Action will be implemented for a period of four years, starting upon the first meeting of the Management Committee in October 2018.