Drug discovery and development is a notoriously lengthy and costly process with a surprisingly low success rate: 90% of drug candidates fail once they reach clinical trials in humans. Despite drug candidates undergoing pre-clinical testing in animal models which aim to recapitulate human diseases and disease-drug interactions, promising drug candidates that are effective and safe in animal models often fail to exhibit the same effect in humans. The reason for this lies in simple biology: animal models are not perfect representatives of humans.
Scientists are of course well aware of the differences in biological systems and signalling networks between animals and humans, and are therefore exploring more biologically relevant alternatives in order to improve the translatability of pre-clinical data to clinical trials in humans. Amongst objectives to improve the efficiency of the drug development process and cut costs also lie environmental and ethical reasons for minimising the use of animals. Fortunately, regulators appear to recognise the inefficiency of the current drug development paradigm and the need for its reformation. This is best exemplified by a momentous update to an 85-year-old US regulation which previously required drugs to be tested on animals before starting clinical trials. The simple yet significant replacement of the word “animal” with “nonclinical tests” by the FDA Modernization Act 2.0 in December 2022 removed the requirement for pre-clinical testing in animals and invites alternative animal-free models to rise to the challenge.
Many biopharmaceutical companies are already prioritising the quest for animal-free models, following the “Three R” ethical principles of animal testing initially proposed by the scholars William Russell and Rex Burch in 1959: replacement, reduction and refinement.3 Animal-free models have progressed vastly since the 3 Rs were established, especially in the past decade. Some of the most promising animal-free models currently in the spotlight are microphysiological systems (MPS) such as organoids and organ-on-a-chip systems. MPS are of particular interest in the context of innovative gene and immuno- therapies, particularly precision medicines, since these are ideally tested on patient-derived cells. As well as providing animal-free means for efficacy and toxicology testing, MPS are valuable tools for research and drug discovery, including next-generation drug screening.
Organoids
Organoids are mini simplified organs that are grown in vitro in 3D cell cultures. They can be derived from embryonic stem cells, pluripotent stem cells or tissue-derived cells, including progenitor or differentiated cells from healthy or diseased tissues, allowing for modelling of a range of organs and tissues including tumours. Unlike standard 2D cell culture models, organoids are able to differentiate into multiple types of tissues which self-organise and mimic in vivo 3D tissue architecture, enabling them to better resemble their in vivo structural and functional phenotype.
Compared with animal models, organoids are cheaper and faster to produce, and have improved viability and durability as well as a higher success rate. However, the universal use of organoids is currently limited by their morphogenetic variability and lack of reproducibility, both in part attributable to difficulties in controlling the cellular microenvironment; and data collation related obstacles. It was through addressing these limitations, and with the help of microtechnology, that the organ-on-a-chip (OoC) was developed.
Organ-on-a-chip (OoC) Systems
OoC systems bring organoid cultures one step closer to native tissues. Unlike the images that may come to mind when picturing an organ-on-a-chip, these microdevices are visually somewhat reminiscent of USB sticks. OoC systems combine cell biology with microtechnology such as microfluidics in order to replicate the physiology of organs, and are able to do so using minute volumes of fluid which mimic blood and fluid flow through vessels and tissues. OoC chips contain microwells and microchannel networks in which stem cell- or organoid-derived cells can reside, and microfluidic systems are used to impose biochemical and physical stimuli tailored to form desirable tissue patterning, for example by controlling concentration gradients and fluid flow. Overall, microtechnologies enable the cellular microenvironment to be closely monitored and controlled, in turn enabling improved control of tissue morphogenesis and reproducibility. Compared with organoids, a huge practical advantage of OoCs is their compatibility with conventional downstream analytical tools and, thanks to advancements in 3D printing techniques and robotics, their potential for mass production and automated operation and analysis.
Scientists have been developing OoCs for a vast variety of organs ranging from the liver, kidneys and heart to the gut, skin and brain, including the blood brain barrier (BBB). Given that humans are multi-organ systems, single-OoCs have even been combined into multi-OoC systems to recapitulate organ-organ interactions and mimic the systemic physiology of the human body. As well as modelling organs and tissues for research purposes, OoC systems can be used to test the efficacy and toxicity of drug candidates including predicting human ADME-Tox (ADME = absorption, distribution, metabolism, and excretion) in pre-clinical trials. Liver OoCs are typically elected for such studies since the liver is responsible for breaking down drugs for excretion. However, in view of the important roles of other organs in metabolism (e.g. the gut and kidneys) and the potential for toxicological side effects to occur in other tissues, scientists are exploring various combined models and eventually hope to move to an easily customisable system.
In light of the demand for more biologically relevant models and the updated pre-clinical testing requirement in the US (a major contributor to the global drug market) it will come as no surprise that interest, innovation and investment in animal-free alternatives is increasing. Naturally, the same can be expected for patent filings. For example, organoid patent filings are reported to be in a stage of exponential growth. Following the success of Sanofi’s therapeutic antibody (SAR445088) for a rare neuromuscular disease, which was granted FDA authorization to enter a phase II clinical trial (NCT04658472) based on efficacy data from an OoC, biopharmaceutical companies are keen to reap similar rewards, some already having announced partnerships with biotech companies developing OoCs. Overall, it seems that the industry is ready for change and animal-free alternatives hold promise for revolutionising pre-clinical research.
We are proud to support Animal Free Research UK, one of the 2023 recipients of our Innovation for All Fund, in their mission to support scientists aiming to replace animal-free models.
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