Beyond animal testing: The rise of organoids in toxicology research

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Around 30% of drugs show adverse reactions during human clinical trials despite promising pre-clinical studies. One of the major causes of the high attrition rate is the poor predictive value of current preclinical models used in drug development. Traditional 2D cell cultures often fail to replicate the cellular complexity of human tissues and show deviations in the expression of human-specific antigens or key transporter proteins. Animal models, on the other hand, do not fully represent human-specific toxicities because of fundamental biological differences between species.

This inefficiency results in substantial financial and temporal costs, with a PhRMA report noting an average R&D cost of about $2.6 billion for bringing a new drug to market, a process extending over a decade. In response to these challenges, the newly passed FDA Modernization Act 2.0 has made a landmark shift by recognising the limitations of animal models and empowering researchers to adopt non-animal methods to demonstrate drug safety and efficacy.

Patient-derived organoids: Accelerating toxicology research without compromising human relevance

The current demand in toxicology research is for a biological model that not only accelerates market entry but also conserves resources, without sacrificing the integrity of human-relevant data. Patient-derived organoids (PDOs) emerge as a superior solution over traditional models. Originating from patient tissues or biopsies, these mini-organs are cultivated into three-dimensional structures leveraging the inherent ability of adult stem cells for self-organisation, self-renewal, and differentiation. Unlike pluripotent stem cell-derived organoids, PDOs do not require additional reprogramming to develop in fully functional mini-organs, hence, preserving the genetic and epigenetic makeup of the patient tissue through passages, including crucial metabolic transporters, and proteins present in the patient’s original tissue. They can be developed from both normal and diseased tissue and remain stable when expanded ex vivo in the lab, offering a distinct advantage for testing off-target and on-target toxicities within the same patient sample. Their adaptability for genetic modifications further positions them as an optimal tool for exploring the mechanisms of action of toxic compounds. In contrast to other human-derived models, PDOs provide a unique combination of biological fidelity, speed, and scalability, positioning them as the preferred choice for early-stage toxicology studies.

Closing the translational gap with HUB organoid technology

HUB Organoids has been spearheading organoid technology, tracing back to the pioneering work in developing the first human organoid from patient-derived tissue in 2011. With the mission to increase the global accessibility of this organoid technology, HUB Organoids has introduced groundbreaking innovations in not just preclinical research, encompassing target discovery, lead identification, optimisation, and toxicology, but also include applications in co-clinical trials and personalised medicine.

Recognising the vital role that early preclinical toxicology studies play in the success of a clinical candidate, we have tailored our toxicology portfolio to meet the needs of drug developers facing challenges at this stage. Our proprietary platform specialises in generating patient-derived organoids (PDOs) biobanks, covering not only human epithelial organs, but also including species commonly used in toxicology studies like dogs, mini pigs, and rats. This unique capability bridges the gap between animal and human data in toxicology studies, providing a critical advantage for pharmaceutical companies to assess the human translatability of their animal studies before enrolling in expensive clinical trials. Additionally, if drug developers encounter toxicity issues in a specific animal species, our technology lets them investigate if these effects occur in other species as well helping them make informed decisions regarding species selection for further testing and reduce and refine animal studies.

Our capabilities offer the flexibility required for innovative toxicology research. We have developed toxicology models, such as the 2D PDO monolayer, which consists of single-layer patient-derived organoids. This unique configuration grants direct access to both the apical and basal sides of the epithelium, which is sometimes required when testing a compound’s effect on gut barrier integrity. Furthermore, we have introduced organoid-based co-cultures with fibroblasts or immune cells, available in both 2D and 3D formats. These co-cultures enable detailed investigation of a compound’s impact within the epithelial microenvironment.

HUB Organoids have proven predictivity of clinical responses. In one study, researchers tested 10 toxic compounds with known clinical outcomes in PDOs. PDOs demonstrated a sensitivity of 83% a specificity of 100%, and reproducibly across seven passages. This signifies the technology’s potential to de-risk drug development by ensuring only the most clinically relevant leads advance to clinical trials.

HUB Organoids is revolutionising drug development with its patient-derived models, offering more accurate predictions and reducing time, risk, and costs. Backed by the FDA Modernization Act 2.0, it’s leading a shift towards efficient, human-focused research, promising faster and more successful treatment advancements.

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