The evolution of disease modelling has seen a paradigm shift from the traditional use of animal models to more advanced in vitro human-based systems. This has been driven by the need for more accurate predictions of human disease mechanisms and drug responses in humans. Advanced in vitro models, including 2D cell cultures, organoids, and organ-on-chip systems, offer a closer simulation to human tissue environments. This article discusses the advantages these models can bring to drug discovery, emphasising their application in complex diseases like fibrosis, or development of ocular therapies. Despite the advancements, challenges such as donor variability, model validation, and the need for greater complexity and reproducibility remain. Continued innovation in combining existing models, refining culture conditions, and integrating modern technologies is crucial for enhancing the predictive power of these models and improving clinical outcomes. Industry has continued investing and there are currently commercially available retinal organoid models that allow for disease modelling and lung fibrosis models that overcome predictivity limitations to accelerate drug development.
Accurate and relevant disease models play a critical role in understanding the disease mechanism for developing targeted, effective therapies in humans. Traditionally, animal models have been crucial for understanding disease mechanisms and predicting treatment outcomes. They help assess the efficacy and safety of new drugs, providing critical insights for regulatory applications and the design of human clinical trials. However, due to significant genetic, anatomical, and physiological differences between animals and humans, animal models can sometimes inaccurately predict human responses to diseases and treatments. For example, thalidomide, an immunomodulatory agent, did not show side effects in animal models but caused birth defects in humans. Consequently, drug development is shifting towards human-based disease models to improve accuracy.
Two-dimensional (2D) cultivated patient-derived cells are an invaluable tool to study disease phenotypes and mechanisms, especially during the early phases of drug development. Donor-derived primary human cells are preferred for their higher genetic heterogeneity compared to immortalised cell lines. Induced pluripotent stem cell (iPSC)-derived lines are also used for disease modelling as they also preserve of donor genetics. Bioengineered tissue models involve cultured tissue pieces or 3D bio-printed mixtures of cells and biomaterials. The main advantage of these 3D models is their ability to better mimic the complex architecture and microenvironment of living tissues, providing more accurate physiological and cellular interactions compared to 2D models. This makes them more representative of in vivo conditions even if they tend to be more heterogenous.
Organoids represent another sophisticated 3D model as they are self-organising structures derived from adult stem cells or induced pluripotent stem cells (iPSCs). In the appropriate culture conditions, these cells spontaneously forming organ-like structures ranging in size from 100 μm for lung organoids, 600 μm for retinal organoids to 2 mm for brain organoids. Organoids from patient-derived IPSCs or from gene-edited iPSCs for inherited disease, replicate the diseased genotype, thus allowing for complex cell pathways to be modelled and accurate drug screening. The industry has invested heavily into validation of iPSC-derived retinal organoids (Figure 1) in 96-well plates format to enable high-throughput drug screening of multiple candidates, making them an ideal platform to obtain predictive data in a physiologically relevant way. Well-validated retinal organoids present of all major retinal cell types and spatial cell arrangement that mimics the native tissue. The retinal organoids also show batch-to-batch consistency with expression of critical markers that define functionality and relevance for disease and drug efficacy studies. Another advantage of disease modelling in retinal organoids is the possibility of performing parallel studies in isogenic cell types like retinal pigment epithelium cells.
Organ-on-chip (OoC) systems are advanced microfluidic platforms that integrate bioengineered or miniaturised tissues or organs connected by 3D microchannels or undergoing fluidic flow. They mimic in vivo functions, biomechanics, and physiological responses, making them useful for disease modelling. However, OoC systems face challenges such as high technical complexity, cost, scalability issues, and difficulties in achieving precise cell placement and density. Additionally, they do not always replicate human organ complexity accurately and generate complex data difficult to interpret.
