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.