Standardized 3D liver toxicity model: Combining unique hESC derived hepatocytes and scaffold technol
|Bidrag från Vinnova
|4 065 000 kronor
|september 2010 - mars 2013
Syfte och mål
The biotechnological and pharmaceutical industries through-out Europe rely on animal-based systems for hepatotoxicity testing (liver toxicity), as an important part of drug development. Today, no commercially available standardized cellular models are adequate to predict human liver toxicity, and this segment is largely occupied by animal experimentation. However, animal models are only about 50 % predictive, causing pharma industry enormous capital loss due to late attrition rates. While human primary hepatocytes as a cellular model have proven to have drawbacks, human stem cell derived hepatocytes are expected to be commonly used in hepatotoxicity testing in the future, since they form three dimensional organ-like structures with improvement of important characteristics when cultured in three dimensional (3D) scaffolds compared to flat 2D cultures. In addition, human embryonic stem cell derived hepatocytes provide an unlimited source of homogenous and functional human hepatocytes. Various scaffolds have been developed independently by different companies, however the major challenge is to select the optimal scaffold for human embryonic stem cells (hESC), and to integrate these scaffolds in a cost-effective in-line production process into a micro-well plate format with small well sizes suitable for High Throughput Screening. The aim of this project is to develop highly innovative, unique and standardized model suitable for high throughput hepatotoxicity screening based on hESC, the complementary expertise of the three project partners, two R&D performing SME´s (Origo Biotech APS, Denmark and Cellartis AB, Sweden) and a technological service partner, Bioneer in Denmark is required.
Resultat och förväntade effekter
A 3D hepatocyte screening platform, which have been validated and benchmarked against existing screening systems. In addition a technological documentation package, that can be used in a CE-mark approval process.
Upplägg och genomförande
In this project cell biologists and material scientists will work together in a commercial focused project and combine unique material properties with hESC-derived hepatocyte cell line in order to develop a 3D toxicity screening platform for preclinical testing of drug candidates. Experimental work is focused on: 1) Evaluation of the optimal combination of scaffold and ESC derived hepatocytes, 2) Development of a standardized screening format, 3) Optimizing analysis methods for 3D screening purposes 4) Validation of the platform with well-described drugs. The research method will be driven by a commercial perspective, meaning that the experimental work done in this consortium is exclusively aiming at providing data and technical documentation, that can be used for validation of the platform and preparation for CE mark of the platform. Partners participating in this project has already made significant progress in establishing a commercial-based starting point for the development of a screening platform