Pharma needs a better way to predict the future or at least a better way to predict, in the early stages of drug discovery and development; which drugs will be winners and which will ultimately fail. Currently, pharmaceutical researchers employ a wide range of preclinical in vitro cell culture tests and in vivo animal models — all of which fail to accurately predict human response a large percentage of the time. Furthermore, these tests and animal models, even when they provide an accurate response, have limited ability to provide any insight into the mechanisms of the response. A researcher may observe an effect, positive or negative, but have no way to understand what the mechanism for this effect is or if this would be seen in a human.
Go With The Flow
Progress is being made in the development of new tools to provide pharmaceutical companies with more predictive technologies. Two of the more interesting approaches, both of which use the concept of maintaining cells in a perfused environment, take very different approaches in how they apply this concept. The first approach, currently being applied to human liver cells, places the cells in a “micro liver platform” which is contained in multiwell plates. Culture medium is allowed to recirculate through connected compartments in the plate. Drugs can be introduced into the medium in the system and the response of the cells analyzed. Early studies have shown that hepatocytes maintain more of their in vivo characteristics for a longer period of time when cultured in this method. This approach has been designed with integration into high throughput screening in mind and thus may be useful in the early screening of compounds for liver toxicity. While this approach may be a step forward in producing more predictive results and being a better tool for screening drugs for liver toxicity, it has limited ability to provide insight into the mechanism of an adverse event.
The second approach, currently being applied to cocultured endothelial cells (ECs) and smooth muscle cells (SMCs) taken from the human (or animal) vasculature, places the cells in a controlled environment where they are exposed to human-derived hemodynamic shear stress forces and other physiologically relevant factors. Similar to the example above, this technology utilizes the concept of “flow” to improve cell survival and biological behavior. However, this approach takes the concept a step further by recreating the hemodynamics that the cells are exposed to while in the human (or animal), including subtle frequency differences that occur in various regions of the body. These region-specific shear stress forces have been shown to be important for replicating cell phenotypes and their biological behavior. In this technology, the cells are also able to communicate through a porous membrane, similar to how ECs and SMCs do in vivo. In this technology, it is possible to independently analyze the outputs from each cell type during or at the end of the experiment. This technology has been shown to be useful in understanding the mechanism of a drug effect (positive or negative), although it does not lend itself to integration with a high throughput system.
In addition to the approaches outlined above, exciting advances are also underway in the areas of 3-D cell-cultures and the use of stem cells in cell-based assays. The use of cell-based assays in drug research is expected to continue to show robust growth as researchers continue to look for more biologically relevant assays and for alternatives to animal models. Undoubtedly, the science will continue to advance and researchers will have more choices in the future, some of which have yet to be discovered. Up until now, there has been an inverse relationship between throughput and physiological relevance in general, the higher the throughput, the less reliable and predictable the assay. As work in this field continues and the demand for better tools and technologies increases, it will be interesting to see if this paradigm continues to hold true.
Dr. Wamhoff is VP of R&D at HemoShear. He cofounded the company and is the co-inventor of HemoShear’s technology. He is an associate professor at the University of Virginia (UVa) and leads an NIH-funded laboratory that studies vascular disease at the Cardiovascular Division of UVa’s Department of Medicine.
SOURCE: HemoShear’s technology