Animal testing has been a major pillar of biomedical research for a few decades now. Recent data from the Animal Use Reporting- EU System (ALURES) shows that in the past several years anywhere between 7.9 and 10.6 million animals have been used annually. The generation of the first “organoid” (Sato et al., 2009) opened an unprecedented opportunity to simulate the human environment more accurately than by utilizing animal models. Depending on the complexity of differentiation protocols it is feasible to generate very intricate in vitro systems that accurately replicate human physiology. Several organoid models have already been successfully applied in research to recapitulate organ function and human physiology, proving to be a valuable tool in science. However, up to date, this concept has not been fully utilized as most proposed systems fail to outline and streamline its use in real-world scenarios. The Blood Vessel Organoid (BVO) model, developed and patented by Angios has been pioneered to accurately represent human vasculature, with its complexity in terms of cell composition and extracellular environment.
Organoid-based research has grown dramatically in the past decade and currently, there are readily available protocols for their generation, use and optimization. In our laboratory, based in Innsbruck, Austria, Angios is extending the use of BVOs from academic research to applied biomedical science and toxicology screening. We will adapt and further develop current imaging methods for efficient use in organoids and facilitate the implementation of this technology in basic and applied biomedical research. This constitutes the transition from the laboratory status to a first-of-its-kind BVO-based toxicity screening service offer in the market.
Background and motivation
Cardiovascular toxicity represents one of the leading causes of clinical trial failure in drug development, accounting for approximately 40% of the drug candidates being withdrawn due to safety concerns. Yet the negative effects on the heart and vasculature are often discovered only at advanced stages after multiple test cycles in animal testing. Rodents are currently the model organism of choice for preclinical toxicity tests during drug development. However, they do not closely resemble the human environment with their physiology, vascular organization, vessel composition and immune system as well as life expectancy and lifestyle substantially differing from humans.
We are developing a toxicity scoring system to assess drug candidates at the preclinical/clinical trial interphase with respect to their effect on human vasculature utilizing an in vitro organoid model. Our predictive score will be designed to reflect the vasculature toxicity data reported for drug candidates that have already gone through clinical trials. The toxicity score can then be used as a predictive tool to assess the potential vasculature toxicity of drugs in development. This project will provide an accurate, worldwide unique, innovative, fast, cost-effective and animal-free model to assess and predict the vascular toxicity of novel drugs before committing to further costly clinical trials, whilst simultaneously reducing the number of animals involved in this stage to zero.
Beyond the scope of this project, a broader area of use cases is conceivable such as local tolerability screening during formulation development, or adaptation of the developed system to support safety for first-in-human trials by investigating local tolerance of intravascular administered drug candidates.
Goals
The main objective of the project is to establish a novel in vitro blood vessel organoid model to assess, score and predict the vascular toxicity of drugs in development in the preclinical stage. The scoring system will rely on human-derived vascular organoids exposed to drug candidates and the analysis of multiple morphology parameters to predict the toxicity of these candidates. We will generate a novel, non-animal tool in biomedical research that can be applied globally for basic pharmaceutical research and drug toxicity testing. With this worldwide unique model, the proposed project lays the foundation for Austrian leadership in organoid-based, animal-free toxicity screening.
Key research content
We will employ and optimize our blood vessel organoid model for use in preclinical vascular toxicity studies. The findings will be used to generate a predictive tool that will accelerate preclinical biomedical research. We will focus solely on vascular toxicity as a main hurdle in preclinical biomedical research and exploit the full potential of BVOs to overcome this obstacle.