rAAV.MRTF-A-based vascular gene therapy in chronic hindlimb ischemia
Peripheral artery disease is a disabling and prognostically unfavorable condition, caused by impairment of lower limb perfusion.
Though narrowing or complete occlusion of a large artery is nowadays treatable by surgical or interventional means (bypasses or ballon angioplasty and stenting, respectively), smaller arteries are not amenable for these techniques. We propose a complementary treatment by growth and maturation of small vessels which are often rarefied or absent due to prolonged hypoxia and /or microvascular inflammation caused by cardiovascular risk factors (diabetes, hyperlipidemia). As an agent to regrow functional microvessel networks, we propose long expressing adeno-associated viral vectors encoding for MRTF-A, a signaling co-factor in the SRF-pathway, which promotes both: proliferation of the microvessels and their stabilisation. This agent will be tested in a pig model of femoral artery occlusion in control and diabetic/hyperlipidemic pigs. An accompanying program is studying side-effects (biodistribution and toxicology).
peripheral artery disease
Generation and functional characterisation of macrophage cell lines from yolk sac precursors
The tissue macrophages in adult organs, including those of the cardiovascular system, mostly originate from embryonic precursors located in the yolk-sac. However, existing macrophage cell lines mostly derive from peripheral blood mononuclear cells or leukemic cells.
Available macrophage cell lines are therefore insufficient to study tissue macrophage functions under culture conditions. The project’s goal is to generate a cell line of bona fide yolk sac-derived macrophage progenitors which can be expanded and differentiated into tissue macrophages. The functions of the macrophages of various origin are to be characterised and compared in vitro and in vivo.
Late pre-clinical development of CD40-TRAF6 inhibitors (TRAF-STOPs)
Blocking the co-stimulatory CD40L-CD40 dyad reduces atherosclerosis. We found that the interaction between CD40 and TNF-receptor-associated factor 6 (TRAF6) is the driving force for atherosclerosis.
Using virtual ligand screening, we identified several small molecule inhibitors termed TRAF-STOPs that were modeled to bind to the CD40-binding domain of TRAF6. Two TRAF-STOPs significantly reduce existing atherosclerosis, improve glucose tolerance and insulin sensitivity in mice, and ameliorate multiple sclerosis. Here we pursue the hypothesis that these TRAF-STOPs are candidates to pass the translational pipeline towards a clinical application to treat chronic inflammatory diseases, including atherosclerosis.Dose finding studies, toxicity and pharmacological safety studies as well as pharmacodynamic studies will be performed, the pharmacological properties will be improved and the proof of the specificity of these small molecule inhibitors will be established
Real-time MRI-guided targeted endomyocardial biopsy of radiofrequency-induced lesions in pigs
The diagnostic benefit of catheter-assisted endocardial myocardial biopsy under fluoroscopy control is mainly limited due to sampling errors.
In a proof-of-concept study in mini pig we were able to show that targeted endocardial myocardial biopsy of acute lesions under real-time MRI has a higher diagnostic accuracy than undirected biopsy under fluoroscopy control. Our goal is to further develop the targeted real-time MRI-guided myocardial biopsy into a clinically safe and fast method. The first milestone of the project will be promoted, in which the mechanical properties of a new MR-suitable bioptome in our animal model will be examined for its equivalent to a conventional biopsy with a steel bioptome. With the same procedural success rate of the new MR-compatible bioptome, the entire project can be continued with the aim of developing it into a clinically relevant procedure.
Re-screening for novel CD40-TRAF6 interaction inhibitors (TRAF-STOPs 2.0)
In this project, we aim to screen for new small molecule inhibitors, which can specifically block the inflammatory signals contributing to atherosclerosis as the dominating cause underlying cardiovascular disease, and may therefore serve as potential drug candidates for anti-inflammatory treatment.
striked out striked out
Transapical mitral-valve stent implantation without using a heart-lung machine
The object of this project is the therapy of mitral-valve insufficiency by means of a transapical mi-tral-valve stent implantation in the beating heart without using a heart-lung machine.
In this project, the design of the stent is supposed to be further developed for the mitral position, so that a greater match with the natural anatomy is attained with a new oval shape. In addition to the apical fixation, another fixation system shall also be developed. The additional anchorage shall ensure the correct anatomical position of the stent.
heart valve disease
Hit-to-lead development of CaMKII-HDAC4 inhibitory compounds to treat heart failure (project 1: Identification of potent hits)
The two proteins calcium/calmodulin-dependent protein kinase II (CaMKII) and histone deacetylase 4 (HDAC4) are formed in the heart. These play essential roles in maintaining the heart's function, but also in the development of diseases.
When the heart becomes diseased, these two proteins bind together. When the binding was inhibited in mice by genetic intervention, the team observed a protective effect against heart failure. In a first high-throughput screening method, which allows the testing of large amounts of chemical compounds, the scientists found inhibitors that prevent the two proteins from binding together. Furthermore, they were also able to demonstrate this inhibition in cells and observe functional effects. These results suggest that the inhibition of the interaction of CaMKII and HDAC4 is a promising therapeutic target. Together with experts from the Lead Discovery Center in Dortmund, the project group would like to identify more targets for these inhibitors in this project with the help of a second high-throughput search procedure. Promising candidates from this and earlier investigations will then be characterised using a cascade of different functional analyses to determine whether they are suitable for further drug development.
Local miR-29b inhibition using drug eluting balloons to block abdominal aortic aneurysm progression
An abdominal aortic aneurysm, which is a vascular “ballooning” of the aorta in the abdomen, is caused by a weak vascular wall. If an aneurysm ruptures, it's often fatal.
The standard therapy is an open or catheter-based surgical procedure to insert vascular supports, so-called stents. It requires rapid intervention and is associated with intensive follow-up and a high long-term complication rate. Among other factors, a micro-ribonucleic acid, miR-29b, is involved in the damage to the vessel wall. Microribonucleic acids are attractive targets for therapeutic approaches. In previous investigations in animal and cell culture models, the team was able to show that inhibitors directed against miR-29b can prevent the development of vascular sacculation.In this project, the feasibility and safety of genetically modified mini-pigs, which serve as animal models for atherosclerosis and advanced vascular diseases, will be investigated. The inhibitor will be delivered directly to the damaged vascular wall via a drug-eluting balloon catheter. This will provide evidence for a possible therapy to limit the progression of aneurysms and reduce the risk of their acute rupture.
abdominal aortic aneurysm
Gene therapy for neonatal sarcomeric cardiomyopathies: towards first-in-patient
One of the most frequent causes of cardiomyopathy in newborns are homozygous or complex heterozygous mutations of the MYBPC3 gene which encodes the cardiac myosin-binding protein C, a protein belonging to the sarcomere.
These congenital cardiomyopathies may rapidly turn into systolic heart failure and in serious cases result in death within the first year of life. Recently, we demonstrated a long-term prevention of the disease using MYBPC3 gene therapy in a homozygous Mybpc3-targeted knock-in mice, which genetically mimic human neonatal cardiomyopathies. In the absence of any treatment options except heart transplantation, gene therapy is a realistic treatment option for this subset of infants with severe and fatal neonatal cardiomyopathy. Our goal is to establish MYBPC3 gene therapy in a large animal model (pig) and thus move another important step closer to clinical application. Such a porcine model, which carries bi-allelic truncating MYBPC3 mutations and displays the cardiac phenotype of the cardiomyopathy in newborns, is not yet available. It will be generated using CRISPR/Cas9-technology, somatic cell nuclear transfer and embryo transfer. Once the porcine model has been successfully developed, the AAV9-mediated, cardiac-specific MYBPC3 gene transfer will be applied. If it turns out to be as successful as in mice, this therapy may perhaps be applied to the little patients in the foreseeable future
In vivo characterisation of the chemokine recep-tor CXCR4 to detect an inflammation in athero-sclerotic plaques by means of PET/MR
It was demonstrated in preliminary studies with animal atherosclerosis models that the radionuclide 68Ga-Pentixafor binds specifically to cells which mediate an inflammation process and thus enables a non-invasive assessment of an inflammation in atherosclerotic plaques.
This project shall carry out the necessary toxicity and dose tests for an initial application in humans. If these tests are successfully completed, the proof of concept shall be demonstrated in patients, whereby it shall be determined whether the incorporated amount of 68Ga-Pentixafor correlates with the expression of CXCR4
CAR inhibitors for the treatment of heart attack
The Coxsackievirus and Adenovirus Receptor (CAR) is a cell contact protein that mediates virus uptake and is essential for early heart development. Mice lacking CAR are protected against Coxsackievirus infection and show hardly any health restrictions.
In a translational approach, we want to investigate CAR as a therapeutic target protein and develop CAR inhibitors for the treatment of heart disease. Building on our initial evaluation of different CAR inhibitors, we will focus on the production and validation of a human anti-CAR antibody. Our aim is to improve the survival of cardiomyocytes, the remodelling processes and the pumping function of the heart. This work includes investigations in the cell culture system, which will then be validated in animal models.We are convinced that CAR is an excellent therapeutic target for heart disease based on (1) the protective effect of CAR deficiency after heart attack, (2) access to inhibitors and (3) the low level of unwanted side effects when CAR is lacking.
Detection of plaque vulnerability with a novel hybrid intravascular NIRF-IVUS imaging system
Atherosclerosis is a chronic inflammation of the vessel wall. Unstable atherosclerotic plaques can rupture and pose a risk of cardiovascular events such as heart attack or stroke.
Despite the progress in cardiovascular imaging techniques, there is no imaging method to distinguish stable from unstable plaques.This project aims to develop a hybrid system for use in medical routine, in which vascular ultrasound and near-infrared fluorescence are coupled. With the hybrid system, molecular parameters of the inflammation can be recorded, and at the same time, the degree of permeability of unstable plaques can be determined. This technology should make it possible to identify patients at risk for further cardiovascular events and intervene early with suitable therapy. The tasks of this translational project include the reduction of the catheter size for hybrid imaging, a preclinical proof-of-concept, investigations on the safety of the technology, and finally, the development of a prototype for clinical studies.
A novel inotropic/lusitropic peptide drug against decompensated chronic heart failure
The objectives of this proposal are the preclinical development of a cardiac-targeted peptide drug with inotropic and lusitropic effects for the short-term intravenous treatment of decompensated chronic heart failure (CHF) and its clinical translation into a first-in-human clinical trial. The life-threatening complication of the clinical syndrome presents a significant unmet medical need given its high mortality and severe adverse effects of clinical drugs to reconstitute cardiac performance.
The proposed therapeutic innovation seeks to exploit a novel regulatory principle to improve cardiac contraction and relaxation by the molecular factor S100A1 and utilizes cell-permeable peptide technology that is derived from the molecule’s C-terminal domain. The translational research project originates from comprehensive preclinical data showing the ability of S100A1ct peptide for a reversible short-term improvement and protection of cardiac performance in vivo and in vitro. In its funded first developmental module, the project seeks to define the therapeutically effective dose-range of S100A1ct in clinically relevant large animal disease models as well as demonstration of toxicological and immunological safety to conclude regulatory steps on ultimate GMP/GLP pre-clinical and clinical development
Low-energy defibrillation of ventricular fibrillati-on in pigs as an animal model for heart failure
In previous studies run by the working group led by Stefan Luther it was shown that the energy applied in cardiac arrhythmias could be reduced by 80 to 90 percent compared to conventional defibrillations.
In order to translate these results successfully into clinical application, the necessary proof of efficacy in an animal model is to be produced in the scope of this project: the termination of ventricular fibrillation by means of a novel defibrillator compared to conventional defibrillation will be examined in pigs used as an animal model for heart failure. The results will constitute the foundation for preparing a study for a first-in-human application
Development of miR-92a inhibitors for the treatment of cardiovascular diseases
Based on own preliminary works that show that miR-92a inhibitors can improve cardiac function after infarction, the safety and optimisation studies necessary for an application in human beings are to be carried out in the context of the application.
For this, the composition of the microRNA inhibitors is to be optimised and the necessary pharmacological and toxicological examinations are to be performed.
acute coronary syndromes, peripheral arterial occlusive disease
IPSC-EHT transplantation for cardiac repair – towards first-in-patient
The mortality rate of patients with end-stage heart failure is high, while treatment options are very limited. The availability of cardiomyocytes, which are obtained from induced pluripotent stem cells, makes it possible to culture artificial heart muscles, which can be used in allogenic transplantation.
It was demonstrated in a guinea-pig myocardial infarction model that the engineered heart tissue (EHT) grows on ailing hearts and improves cardiac function. This project intends to determine the minimal effective dose/size of the engineered heart tissue, and study the growth of artificial cells and the size of the engineered heart tissue. Lastly, the trials will be repeated using a porcine animal model.
GMP-production of engineered human myocardium for heart failure repair
Irreversible and progressive loss of cardiomyocytes is the underlying cause of heart failure. Remuscularization of the failing heart can be achieved by epicardial implantation of tissue engineered myocardium.
A major procedural challenge for the translation of cell based therapies is the set-up and validation of a cGMP-production process. This should be done early during the translation process to reduce costs and variability/inconsistency already in preclinical studies and facilitate clinical translation into first-in patient studies. We have developed a versatile protocol for the construction of engineered human myocardium from ESCs and iPSCs to meet cGMP demands. The objectives of this project are to now set-up a GMP production pipeline and obtain a manufacturing authorization from the local competent authority for the preparation of EHM for a first in patient safety study with an anticipated number of 10 patients with end-stage heart failure
Gene Therapy of Cardiac Hypertrophy
The project wants to test a novel therapeutic approach in a pig model of acquired cardiac hypertrophy using inhibition of the transcription factor NFAT, which has been shown to control the hypertrophic gene programme in aortic stenosis but also hereditary forms of cardiac hypertrophy.
Cardiac hypertrophy can be caused by obstruction of the aortic valve or by hereditary diseases of the heart muscle. With disease progression, cardiac hypertrophy results frequently in heart failure that may persist even after treatment of underlying causes. In both hereditary forms and acquired forms of cardiac hypertrophy, treatment options are limited. Therefore, we want to test a novel therapeutic approach in a pig model of acquired cardiac hypertrophy using inhibition of the transcription factor NFAT, that has been shown to control the hypertrophic gene programme in aortic stenosis but also hereditary forms of cardiac hypertrophy.
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