Translational Cardiology

Sprache-deutsch_580x208 German Version

Our working group was established within a professorship of the German Centre for Cardiovascular Resserach (DZHK) and focuses on identification and validation of novel therapeutic targets for treatment of heart failure, but also rare genetic causes of cardiovascular diseases such as cardiomyopathies and the Marfan syndrome).

We use adeno-associated virus (AAV) vectors for targeted and efficient transfer of genetic material into the myocardium or vascular wall.

Projects

Development of improved adeno-associated virus (AAV) vectors for cardiovascular gene transfer

AG_Müller_Abb1 Figure 1. Intravenous injection of optimized Adeno-associated viral vectors for targeted expression in the heart. The figure shows the detection of the enhanced light-emission signal specifically in the heart area of an anaesthetized mouse as a result of the efficient expression of a reporter gene transferred by an optimized AAV. The gene transfer is detectable for over 9 months.

Gene therapy approaches are increasingly based on AAVs since they do not lead to any known diseases. By virtue of their wide tropism, AAV vectors can be absorbed by a large number of different tissues, including non-desired ones. This means that AAV vectors can still lead to off-target gene expression, which might cause deleterious side effects. This hurdle could be overcome by the use of tissue specific, cardiac and vascular, regulatory elements (promoter, miR target sites) in the expression cassette, which could restrict expression in the desired cardiac and vascular tissues.

The efficiency and specificity of the AAV-mediated gene transfer can be also improved by the targeted modification of the viral capsid surface or the use of alternative AAV serotypes. In parallel with the optimization of cardiac gene transfer, endothelial cells being refractory to transduction, we also pursue the development of approaches to increase the efficiency of endothelial gene transfer. The failure of alternative serotypes to efficiently transduce endothelial cells motivated the development of another approach, the display of novel random peptide libraries on AAV2 and recently AAV9, mediated by their insertion in the AAV2 capsid surface area known to bind to the AAV2 primary receptor and the corresponding one in AAV9. The selection of the randomized AAV peptide libraries in primary human endothelial cells lead to the identification of efficient and specific for endothelial cell transduction vectors (Müller et al. 2003, Varadi et al. 2012). In addition to the AAV-library selection approach for the transduction of other cardiac cell types, we also investigate the potential of targeted AAV capsid modifications for the reduction of immunogenicity.

Novel therapeutic approaches for heart failure

Based on comprehensive analyses of metabolic alterations in heart failure we are characterizing novel targets for therapeutic interventions. Of particular interest are epigentic mechanisms of metabolic remodeling which could be translated into novel therapeutic strategies.

Novel therapeutic strategies for cardiomyopathies with a particular focus on neuromuscular diseases

Cardiomyopathies are frequently observed in patients with muscular dystrophies. Since current treatment strategies are very limited, we are developing novel gene therapy approaches for cardiomyopathies in Duchenne muscular dystrophy and myofibrillar myopathy due to mutations in the gene encoding desmin.

Novel therapies for Marfan syndrome

Marfan syndrome (MFS) is a rare genetic disease of the connective tissue affecting the eye, lung and large vessels. Patients are threatened by aortic aneurysms which are prone to rupture. Novel therapies are needed for this devastating vascular disease. Thus, we are working on gene therapy approaches to inhibit remodeling processes oft he aorta.

Novel therapeutic approaches in pulmonary hypertension

In pulmonary hypertension, chronic inflammatory reactions occur due to various causes, resulting in a remodeling of the wall of pulmonary arteries thus increasing stress on the right ventricle. Since therapeutic options are very limited, we are investigating novel approaches targeted on inhibition of the chronic inflammatory processes.


Research Support

Our research is supported by the German Centre for Cardiovascular research (DZHK), the Bundesministerium für Bildung und Forschung, the Deutsche Forschungsgemeinschaft (DFG), and the European Commission (Horizon 2020).

Doctoral thesis

Several MD and PhD students have succesfully prepared a thesis in our group within the last 15 years. We thus encourage applications of students with strong interest in translational cardiovascular research.

Team

Prof. Dr. med. Oliver Müller

Bereichsleitung Angiologie, Facharzt für Innere Medizin, Kardiologie und Angiologie
Tel.: 0431 500-22950Fax: 22954

Dr. rer. nat. Anca Remes, M.Sc.

Wissenschaftliche Mitarbeiterin, Postdoc
Tel.: 0431 500-22961

Wiona Burmeister

Technische Mitarbeiterin/ Technician, CTA
Tel.: 0431 500-22943

Angela Lorenzen

Technische Mitarbeiterin/ Technician, MTA
Tel.: 0431 500-22929

Dr. med. vet. Nesrin Schmiedel

Wissenschaftliche Mitarbeiterin, Postdoc
Tel.: 0431 500-22936

PhD students

Christopher Borowski, M.Sc.

Wissenschaftlicher Mitarbeiter, Doktorand/ PhD student
Tel.: 0431 500-22966

Dima Ibrahim Basha, M.Sc.

Wissenschaftliche Mitarbeiterin, Doktorand/ PhD student
Tel.: 0431 500-22936

Leonard Hüttermann, M.Sc.

Wissenschaftlicher Mitarbeiter, Doktorand/ PhD student
Tel.: 0431 500-22962

Andrea Matzen

Wissenschaftliche Mitarbeiterin, Doktorand/ PhD student
Tel.: 0431 500-22936

Pia Steinkuhl

Wissenschaftliche Mitarbeiterin, Doktorand/ PhD student
Tel.: 0431 500-22963

MD students

Alan Yoab Mogollon Marquez (mogollon@outlook.de)

Thilo Nitsche; Thilo Nitsche (Thilo.Nitsche@uksh.de)

Marie Noormalal (marie.noormalal@uksh.de)

Publications