Human disease models in drug development

Abstract

Biomedical research is undergoing a paradigm shift towards approaches centred on human disease models owing to the notoriously high failure rates of the current drug development process. Major drivers for this transition are the limitations of animal models, which, despite remaining the gold standard in basic and preclinical research, suffer from interspecies differences and poor prediction of human physiological and pathological conditions. To bridge this translational gap, bioengineered human disease models with high clinical mimicry are being developed. In this Review, we discuss preclinical and clinical studies that benefited from these models, focusing on organoids, bioengineered tissue models and organs-on-chips. Furthermore, we provide a high-level design framework to facilitate clinical translation and accelerate drug development using bioengineered human disease models.

Keywords: Molecular medicine; Translational research.

Fig. 1. Drug development pipeline.

Current development pipeline of new drugs with proven preclinical safety and efficacy in animal models. The average duration of the different (pre-)clinical stages, the percentage of drugs (averaged over the past 5 years) that move to the next phase and the median costs of the different stages per drug are illustrated^,.

Fig. 2. Overview of different disease models.

From left to right, bioengineered models are ordered from the least to the most complex, including their advantages, limitations and stage of application during the drug development process. iPS cell, induced pluripotent stem cell.

Fig. 3. Schematic overview of a rational design of a disease model that incorporates different similarity criteria to ensure model scalability.

The flow chart shows the most important design considerations and workflows required for bioengineering human disease model. ECM, extracellular matrix.