The pharmaceutical industry is continually challenged by high attrition rates (> 90 %) as drug candidates progress from discovery, through clinical trials and to market. Neurodegenerative disease research, for example, is well known for late-stage failures due to the limitations of traditional drug development pipelines, which rely heavily on in vitro and in vivo animal testing. These bottlenecks can be attributed to the inherent limitations of each method, with in vitro models often failing to capture the complexity of living organisms, and in vivo models being too costly and time-consuming for early-stage testing of lead molecules. Integrating Caenorhabditis elegans (C. elegans) early into these pipelines, by running concurrently with in vitro testing, offers a solution by allowing earlier detection of potential failures, thereby reducing time and costs. This integration provides a more nuanced approach to drug discovery, where both the cellular and whole-organism level response to the compounds is considered in tandem, offering a clearer picture of the potential success or failure of a compound.
The Bottleneck in Drug Discovery: Transitioning from In Vitro to In Vivo Testing
One of the most significant challenges in drug discovery is the transition from in vitro (cell-based) models to in vivo (animalbased) models. In vitro testing is invaluable for its ability to screen large numbers of compounds quickly and cost-effectively, providing detailed insights into the biochemical and cellular effects of potential drugs. However, these models lack the complexity of an entire living organism, where factors such as metabolism, intra-tissue interactions, and whole-organism physiological processes can be considered. As a result, many compounds that perform well in vitro fail in subsequent in vivo tests, leading to wasted time and resources.
The use of C. elegans as a model organism offers a promising solution. With its simple anatomy, well-understood genome, and significant genetic similarity to humans, C. elegans provides an efficient and ethically acceptable model for early-stage in vivo testing. By incorporating C. elegans into the pipeline, researchers can observe whole-organism effects early on, allowing for better prioritisation of compounds before they advance to more complex and costly studies in mammalian animal models.
Integrating In Vivo and In Vitro Testing: A Synergistic Approach Data from C. elegans experiments provide different forms of information than data obtained only from in vitro experiments in human cell lines, adding to the predictive power of early-stage drug discovery. The data can be used to inform decision-making, or at a greater scale, to train machine-learning approaches. Compounds that show positive results in both in vitro assays and C. elegans models are more likely to succeed in subsequent stages of testing. This synergy allows for refining selection criteria, ensuring that only the most promising candidates progress to mammalian studies. By doing so, the overall number of mammals used in testing is reduced, aligning with the 3Rs principle of minimising animal use while maximising research efficiency, ultimately accelerating the drug discovery process and reducing the likelihood of costly late-stage failures.
