RETHINKING DRUG DEVELOPMENT – IMPROVING TRANSLATIONAL RESEARCH

Monika Schäfer-Korting

Freie Universität Berlin, Berlin, Germany

Abstract

In the European Union, hazard analysis of cosmetics and their ingredients in animal testing is prohibited and priority is given to non-animal (alternative) approaches in the testing of chemicals (REACH; registration, evaluation, (rejection,) and approval of chemicals). This has strongly enhanced the development of computational (in silico) and in vitro approaches for, but not exclusively in, the field of toxicology. In fact, several in vitro approaches can also be used in fundamental research and drug development. Testing in complex 3D cell cultures (i.e. organoids) appears most promising in this regard. This holds true the more because the construction of organoids is not limited to models of normal organ function. For example, genetic diseases can be modeled by gene silencing or gene transfer, cytokine exposure of the culture allows to model inflammatory diseases and cocultures with tumor cells to generate cancer models. Using primary cells of human origin allows to overcome species related differences which contribute to failures in translational medicine. Models built using cells from several donors introduce diversity which is most often neglected in animal studies. Recent results indicate the approach to be suitable for the evaluation of both new drugs and drug carrier systems.

The “human-on-the-chip” approach allows cross-talk not only by the various cell types building a single organ, but also enables several (currently up to four) organs to jointly influence the pharmacokinetics and pharmacodynamics. 3D printers bear the potential for a future organ reconstruction outstanding in quality and at high rate.

Many studies, exemplified here based on 3D skin models and drugs for skin diseases, indicate the value of the implementation of in silico approaches and the testing in organoid cell cultures. Integrated into drug development for the identification of most suitable substances and drug delivery systems, poorly performing approaches can be eliminated from further testing in an early stage and final tests in the animal can focus on the most promising candidates. This should improve the success rate in translational research and may allow cost cutting. Moreover, reshaping the processes in drug development offers the potential to reduce testing in the animal, too. The implementation of this approach, however, will significantly increase the need for human cells. To cover the demand, tissue banking as well as the use of induced pluripotent stem cells has to be investigated. Sharing these cells in several labs will serve as quality control.