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How Organoids Can Take Your Drug Candidates Further

This blog post was written in partnership with STEMCELL Technologies, who provide cell isolation products, specialized cell culture media, primary cells, and supporting reagents for use in life sciences research across the basic to translational research continuum. STEMCELL Technologies’ in-house Contract Assay Services (CAS) work with you to design and perform in vitro potency and safety studies for drug discovery and development. Their services are available on the marketplace.

Bringing a drug candidate to market can often result in unexpected clinical outcomes due to unrepresentative data being used in key decision-making steps. Many of the inefficiencies found throughout this process can be directly linked to the substantial lack of physiologically relevant preclinical models.1 With the passing of the FDA Modernization Act 2.0 in December 2022, the appetite for more clinically predictive tools has increased significantly. This new guideline aims to facilitate progress toward replacing animal use in biomedical research and outlines new approach methods (NAMs) that may be used to reduce or replace conventional animal studies.2 Among NAMs, organoid technology has provided an opportunity for pharmaceutical companies to more faithfully model human biology by recapitulating the complex, physiological properties of the represented organ.

Organoids are three-dimensional tissue cultures, characterized by their ability to self-organize multiple, organ-specific cell types into structures similar to what is observed in vivo (Figure 1).3 Compared to traditional two-dimensional (2D) culture, organoids provide a more physiologically relevant model system that recapitulates the tissue of origin across a large number of passages. By faithfully maintaining the presence of specialized cell types, organoids provide a stable platform to simulate the unique biological characteristics and function of both healthy and diseased primary organ tissues, providing a human-relevant model system that lends itself well through many stages of the drug discovery and development process.

Figure 1. Intestinal Organoids Contain Mature Cell Types Following Differentiation
(A, B) Organoids grown in IntestiCult™ Organoid Growth Medium are enriched for Ki-67+ proliferative cells while containing few differentiated cell types such as goblet cells (MUC2), enterocytes (KRT20) and enteroendocrine cells (CHGA). (C, D) When switched to IntestiCult™ Organoid Differentiation Medium, organoids contain a small number of Ki-67+ proliferative cells (orange arrows), with more physiological proportions of goblet cells (MUC2), enterocytes (KRT20) and chromogranin A- (CHGA-) positive enteroendocrine cells (green arrow).

One of the applications of organoids in drug research includes preclinical toxicity testing and safety evaluations. Data gathered during this stage of drug development is essential and serves to identify potential adverse effects of a therapeutic agent. Despite proven efficacy and safety in 2D culture and animal models, most drugs fail in clinical trials indicating a significant translational gap, emphasizing the need for human-relevant model systems. This is because 2D models and animal-derived data often fail to reflect the complexity of in vivo human conditions, offering low predictive value of clinical outcomes and hindering the advancement of promising drug candidates into later stages of clinical trials.

The most common reason why therapeutic leads drop out is mainly due to their failure in safety and efficacy testing;4 an estimated 22% of clinical trial failures and 32% of market withdrawals of therapeutics are due to hepatotoxicity.5 Human liver organoids (HLOs) are increasingly being used to generate preclinical data to predict the risk of drug-induced liver injury (DILI) of therapeutic compounds. In a study conducted by Zhang et al., the authors found that high-throughput and on-chip HLO systems exhibited enhanced in vivo-like functions and were amenable to DILI risk evaluations. Additionally, the on-chip HLO model was able to predict the synergistic hepatotoxicity of using tenofovir and inarigivir as a combination therapy to treat Hepatitis B Virus (HBV) and reflect the clinical manifestation of DILI observed in patients.5 Another study developed an HLO-based assay with multiplexed readouts that include viability, cholestatic and mitochondrial toxicity with high predictive values for 238 marketed drugs at 4 different concentrations.1 This HLO-based toxicity screen was able to predict a genomic predisposition (CYP2C92) for DILI caused by Bosentan medication and can further be developed into assays for compound optimization, mechanistic study and personalized medicine. To learn more about using liver organoids for hepatotoxicity assessments, watch our webinar on Predictive In Vitro Models for Toxicity Testing and Liver Research.

The application of organoid models in toxicity testing is not only limited to liver research but also includes many organs essential for the pharmacokinetic pathway (ADME). Drug-induced gastrointestinal toxicities (GITs) are one of the least likely causes of attrition in the preclinical phase despite them being the most common adverse effect seen in clinical trials.6 This current paradigm of safety assessment results in passing the liabilities onto the patient, forcing them to bear the burden of reduced quality of life. In an ideal scenario, GITs would be identified early and screened out with human-relevant models capable of predicting clinical outcomes. Takahashi et al. were able to develop a drug cytotoxicity assay using human intestinal organoids in monolayer culture. The authors performed a compound screen and identified compounds with higher cytotoxic activity against organoid-derived intestinal epithelial cells (IECs) than Caco-2 cells, while further elucidating the mechanism of action of YC-1.7 This new methodology highlights the differences in intracellular signaling pathways between Caco-2 cells and normal IECs, suggesting potential applications of this assay for GIT screening. To incorporate intestinal organoids in GIT screening, view our protocol on Toxicity Testing for Drug Development Using Human Intestinal Organoids and IntestiCult™.

In the metabolism and excretion stages of the pharmacokinetic pathway, the kidneys can be susceptible to drug-induced nephrotoxicity. In a study by Lawrence et al., the authors developed a predictive assay by identifying HMOX1 as a useful marker for toxic stress and engineered HMOX1-reporter renal organoids as screening tools. When exposed to a panel of blind-coded nephrotoxic and non-toxic compounds, they found that the reporter-organoids were able to predict the toxicity of the known nephrotoxic agents successfully.8 Although some limitations exist with the assay, the results offer a promising starting point to guide the development of future stress-reporting organoid assays for drug development.

Outside of the ADME pathway, neural organoids play an essential role in brain disease research and drug evaluation. Neurological disorders are some of the most challenging therapeutic areas for successful drug approvals, presenting an urgent need to advance new and innovative drug development tools. Yokoi et al. were able to develop a method for preclinical seizure liability assessment and screening of antiepileptic drugs (AEDs) by focusing on signal components < 500 Hz in iPSC-derived neural organoids using planer microelectrode arrays (MEAs).9 Organoid response to convulsants was evaluated and resulted in sudden and persistent seizure-like firing, whereas in the administration of AEDs, the frequency of oscillation decreased in a concentration-dependent manner. This study suggests that analysis of frequency components of neural organoids is an effective assessment of seizure liability of drugs and AEDs and can further be developed to study the treatment of various neurological diseases. To bring more insights on neural research into your lab, request a free wallchart summarizing the applications and challenges of developing human neural organoids.

In conclusion, organoids have shown great potential in preclinical toxicity testing and safety evaluations for drug development. Having a more physiologically relevant system is key to helping close the translational gap and accelerate the delivery of effective therapies to patients in need. When creating strategies to solve the most complex problems in drug development, having the right tools and resources that can keep up with your ideas is essential to maximize efficiency. STEMCELL Technologies can support every stage of your research with optimized organoid media kits, training programs and additional resources found in our Organoid Research Learning Center. For more information on choosing the right media kit for you, or to learn more about organoids in drug discovery, Contact Our Organoid Specialists or Request a Seminar to connect with our organoid team.

  1. Shinozawa T et al. (2021) High-fidelity drug-induced liver injury screen using human pluripotent stem cell-derived organoids. Gastroenterology 160(3): 831 – 846.
  2. Stresser DM et al. (2023) Towards in vitro models for reducing or replacing the use of animals in drug testing. Nat Biomed Eng: 1 – 6.
  3. Yang S et al. (2023) Organoids: The current status and biomedical applications. MedComm 4(3).
  4. Zietek T et al. (2021) Drug screening, oral bioavailability and regulatory aspects: A need for human organoids. Pharmaceutics 13(8): 1280.
  5. Zhang CJ et al. (2023) A human liver organoid screening platform for DILI risk prediction. JHEP 78(5): 998 – 1006.
  6. Peters MF et al. (2020) Developing in vitro assays to transform gastrointestinal safety assessment: Potential for microphysiological systems. Lab Chip 20(7): 1177 – 1190.
  7. Takahashi Y et al. (2023) Drug cytotoxicity screening using human intestinal organoids propagated with extensive cost-reduction strategies. Sci Rep 13(1): 5407.
  8. Lawrence ML et al. (2022) Human iPSC-derived renal organoids engineered to report oxidative stress can predict drug-induced toxicity. iScience 25(3).
  9. Yokoi R et al. (2021) Analysis of signal components < 500 Hz in brain organoids coupled to microelectrode arrays: A reliable test-bed for preclinical seizure liability assessment of drugs and screening of antiepileptic drugs. Biochem Biophys Rep 28: 101148.