Drug discovery screening using organoids

The importance of organoids in drug discovery screening

While conventional 2D cell culture has advantages such as low cost and simplicity, it has faced challenges in accurately reproducing the complex tissue structures and functions found in living organisms, and has shown limited predictability in clinical trials.

In contrast, 3D organoids created from stem cells can more faithfully reproduce the structure and function of organs. Therefore, they can provide models with physiological functions closer to those of living organisms, offering advantages such as enabling more accurate predictions of human tissue responses.

Latest Technologies and Automated Workflows for Organoid Screening

Automation system

Organoids are indispensable for modeling diseases and evaluating the effects of compounds. Within this field, automated integrated systems are being developed that can automatically monitor and maintain the growth and differentiation of organoids and stem cells, as well as test their performance characteristics and the effects of various compounds.

This system consists of the ImageXpress® Confocal HT.ai system and analysis software, an automated CO₂ incubator, a Biomek i7 liquid handler, and a collaborative robot rail, in addition to optional components such as an automated centrifuge, an ImageXpress® Pico system, and a plate reader.

AI image analysis

In recent years, the impact of CAR-T cells on the morphology of cancer organoids has become clear. The use of AI-based image analysis tools now makes it possible to quantitatively evaluate treatment efficacy by tracking changes in organoid shape, size, and survival rate over time.

High throughput

The transition to high-throughput screening, utilizing tools such as 384-well plates, is also a key point. While High-Throughput Screening (HTS) employs automated equipment to rapidly test thousands to millions of samples, it plays a crucial role in assays for various biological processes, including drug discovery, apoptosis, cytotoxicity, and cell proliferation.

Success Stories of Drug Discovery Research Using Organoids by Disease

Research examples related to the digestive system (enteritis)

This is a case where compounds (such as glycyrrhizin) that inhibit TNF-dependent cell death, which was difficult to identify with existing models, were identified using human small intestinal organoids. It has been clarified that glycyrrhizin inhibits cell death by suppressing the caspase-8-dependent apoptotic signaling pathway. Furthermore, it has been confirmed that glycyrrhizin also shows an improvement effect on enteritis in enteritis model mice.

Oncology (Cancer)

InnoSer's high-throughput phenotypic screening service for organoids can accelerate the lead compound selection and optimization process by providing data using patient-derived organoids (PDOs).

Furthermore, automated, label-free screening combining the University of Antwerp's screening platform "DrugVision.ai" with Orbits Oncology's image and data analysis technology enables acquisition of insights into drug efficacy, mechanism of action, and synergistic effects. This allows for data-driven rapid decision-making while comparing multiple lead compounds.

Respiratory system (lungs)

3D lung organoids generated from human lung epithelial cells cultured in Matrigel supplemented with growth factors were monitored under transmitted light, stained, and then imaged through the Matrigel using automated confocal imaging. While conventional and AI tools are used for image analysis, advanced image analysis enables complex analyses of organoid 3D reconstruction, cell morphology, viability, and differentiation markers. Furthermore, concentration-dependent effects of multiple drugs causing pulmonary toxicity have been measured.

Incorporating organoids into drug discovery screening

Cultivation/Induction

After differentiation induction, iPS cells are induced to self-organize. Patient tissues and epithelial cells are cultured in media containing growth factors after separating tissue pieces and enzymatic treatment. By embedding these in ECM such as Matrigel at low temperatures and gelling at 37℃, the 3D structure is stabilized. This makes it easier to reproduce in vivo-like polarity and lumen formation.

Evaluation metrics

For evaluation, methods such as ATP measurement for cell viability, as well as image analysis to track changes in proliferation rate and size, are widely used. Normalized Organoid Growth Rate (NOGR) is an index that normalizes growth rate from bright-field images, allowing for precise separation and quantification of cytotoxicity and proliferation inhibition. This can lead to more accurate drug response and phenotypic evaluations.

What will happen with organoid technology in the future?

Personalized medicine

PDO, which reflects a patient's individual treatment history and genetic variations, enables prior comparative evaluation of drug responses in a more biologically relevant environment. This allows for narrowing down highly effective treatments and predicting drug resistance, which is expected to lead to tailored treatment selections for patients.

Animal Experiment Alternatives (3Rs)

Organoids can reproduce human-specific drug responses in a dish. Therefore, they can be said to be a powerful alternative model for promoting the 3Rs (Replacement, Reduction, and Refinement) in animal testing. In Japan, the proper implementation of animal testing is strongly required, and "AAALAC accreditation (a voluntary third-party accreditation program)" is drawing attention as it ensures international standards of animal welfare and humane treatment.

CRO utilization

By utilizing specialized oncology CRO services, you can outsource the efficacy and toxicity evaluation of organoids, which requires advanced expertise, thereby increasing the efficiency of candidate compound screening. From this perspective, you can selectively choose preclinical studies, leading to accelerated new drug development.