Projekte

Cardiosensor: organotypische menschliche Herzkulturen

Ein neues In-vitro-Testsystem für Pharmaka soll die Analyse von Nebenwirkungen auf menschliches Herzgewebe verbessern.

Projektname: Humaner Cardiosensor
Organotypische menschliche Herzkulturen: Entwicklung eines in vitro Testsystems zu Evaluierung von Pharmakanebenwirkungen auf die Aktivität von humanem Herzgewebe
Projektleiter: Prof.Dr. Elke Guenther
Geldgeber: BMBF
Projektträger: DLR
FKZ: 01GG0710
Laufzeit von: 01.11.2007
Laufzeit bis: 31.10.2010

Pharmaka werden bei der Wirkstoffentwicklung und im Rahmen der Sicherheitspharmakologie auf ihre Nebenwirkungen auf menschliches Herzgewebe getestet. Da natürliches menschliches Testgewebe nur sehr eingeschränkt zur Verfügung steht, wurde bisher vielfach auf Tierversuche zurückgegriffen. Ein neues Testsystem auf der Basis von Gewebekulturen menschlicher Herzzellen bietet eine sinnvolle und kostengünstige Alternative. Die Aktivität der Ionenkanäle in den Zellmembranen spiegelt die elektrische Erregbarkeit und Funktionalität der Herzmuskelzellen wieder. Elektrophysiologische Analysen werden deshalb für das neue Testverfahren optimiert.

Beschreibung

One of the main problems in the development of drugs within the area of cardiovascular diseases is the very limited amount of assays with direct significance for the human pathophysiological situation. For the electrical excitability of cardiomyocytes it is for example well known that the ion channels involved exhibit great variations within different mammalian species. Furthermore, the subset of ion channels expressed varies within different regions of the heart (i.e. atrium vs. ventricle; epi- vs. endocard). This leads to profound limitations of preclinical models with respect to their significance for the situation observed in humans. Accordingly there is a great need for preclinical models, which reflect more the physiological and pathophysiological situation found in humans. In addition, most model systems used for the development of drugs within the cardiovascular field are acute preparations often only lasting for a few hours, which results in a great number of animals needed for these studies. Therefore a new assay system developed from human tissue with a lifetime of days to weeks not only would reflect much more the (patho-) physiology of human heart cells but would also reduce the amount of animals needed for the development of these drugs.
The concept of this consortium is to establish organotypic heart cell cultures from human origin as a new test system for preclinical drug development and safety pharmacology testing. Based on acute slice preparations and stem cells, organotypic human heart cell cultures will be developed and validated for the prediction of drug action and safety. Cryopreservation of these tissue cultures and the implementation of these cells in new screening methods will be evaluated. Due to their human origin these cultures will have a direct significance for clinical testing and the aim is to establish cultures which can be used for up to several weeks. The development of such organotypic human heart cell cultures will allow performing long-term test series with a low amount of preparations needed.
With the planned work, organotypic cultures from human heart tissue will for the first time become available for pharmacological research. It is expected that a major breakthrough for safety pharmacology testing and preclinical drug development can be achieved. New technologies of tissue slicing will provide a preparation that for long has been regarded as unapplicable to heart tissues. Methods of cardiac differentiation of human embryonal stem cells have only recently become available, and this will be the first endeavor to validate the resulting tissues for pharmacological research. As such, we will be able to utilize tissues with the highest degree of differentiation (adult slices) along with those providing the highest flexibility and availability in the future (stem cells).
This approach can be expected to yield research models with unprecedented relevance and standardization, the two most crucial requirements.

Projektpartner

  • Fraunhofer Institut für Fraunhofer-Institut für. Biomedizinische Technik (IBMT), St. Ingbert
  • Fraunhofer-Einrichtung für Marine Biotechnologie (EMB)
  • Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Universität Lübeck
  • Institut für Neurophysiologie, Universität Köln
  • Sanofi-Aventis, Frankfurt

Veröffentlichungen

Meyer T, Stuerz K, Guenther E, Edamura M, Kraushaar U. (2010) Cardiac slices as a predictive tool for arrhythmogenic potential of drugs and chemicals. Expert Opin Drug Metab Toxicol. 6(12):1461-75. Review.

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