Adverse drug reactions (ADRs) are the unexpected side effects of drugs. They are classified as predictable or unpredictable drug-induced injury, which may occur after a single or prolonged exposure to one or multiple compounds. Historically, toxicology research has relied heavily on animal models to understand and characterize the toxicity of novel compounds. However, animal models are imperfect proxies for human toxicity, and there have been several compelling cases where animal models cannot predict human toxicity, highlighting the need for improved predictive models of human toxicity. As a result, stem cell-derived organoids are under investigation as potential models for toxicity during early stages of drug development.
Organoids are three-dimensional (3D) self-aggregating structures generated from stem cells or progenitor cells in a process that recapitulates molecular and cellular stages of early organ development. The differentiation process leads to the appearance of specialized mature cells and is connected with changes in the organoid internal structure rearrangement and self-organization. The formation of organ-specific structures in vitro with highly ordered architecture is also strongly influenced by the extracellular matrix. These characteristics make organoids a powerful model for in vitro toxicology.
Hepatotoxicity
In terms of drug metabolism, the liver is the most important organ. This is due to the robust expression of both phase I and II metabolism enzymes, such as cytochrome p450s and transferases that modify xenobiotic compounds into excretable forms. Hepatoxicity is the leading cause of attrition in drug development. Although human primary hepatocytes (hPH) are not a flawless model, they are still considered the gold standard for studying hepatotoxicity in vitro. The major limitation of using hPH is that they rapidly dedifferentiate after the tissue is removed from the patient's blood supply. To overcome the limitations of hPH stability in vitro, a more physiologically relevant and stable model is needed to measure the long-term effects of drug-induced toxicity.
Organoid models are being developed in the hope that they will improve upon current 3D models. When compared with hPH, human liver organoids showed far greater urea and albumin production, indicating that organoids have greater physiological relevance than traditional 2D culture systems.
Cardiotoxicity
Cardiotoxicity accounts for 31% of all adverse drug reactions, most of which affect either calcium or potassium channels, resulting in arrhythmias. Several models have been created to test cytotoxicity resulting from impaired channel function in vitro, but these models are generally comprised of a single cell type. Therefore, there is an urgent need to develop a reliable platform for testing drug efficacy and toxicity. Recent developments in using organoids derived from human induced pluripotent stem cells in cardiotoxicity and drug efficacy tests have provide a potential solution to address this problem.
OrganoLab has previously developed a human cardiac organoid platform that provides functional contractile tissue with biological properties similar to native heart tissue, including mature, cell-cycle-arrested cardiomyocytes.
Gastrointestinal toxicity
The gastrointestinal (GI) tract plays an important role in xenobiotic bioactivation, metabolism and detoxification, as it is rich in xenobiotic processing proteins. GI toxicity is a common and often severe dose limiting side effect of conventional chemotherapy and the recent "targeted" therapies that cause adverse "off tissue" responses. Symptoms usually include diarrhea, dehydration and ulceration, leading to increased susceptibility to infection, due in part to impaired barrier function as a result of damage to the crypt and/or villus structures. As improvements in oncology therapeutics are pursued to acquire more efficacious agents, assessment of their potential GI toxicity remains crucial.
OrganoLab has further developed and validated the organoid model as a screening tool to predict GI toxicity and subsequent mucosal regeneration. The GI organoids are well established, characterized and have a relatable metabolic profile compared with donor matched tissue.
Nephrotoxicity
The kidney's specialized role in filtering substances from the blood to maintain volume and electrolyte homeostasis, coupled with the high metabolic activity of the renal tubule epithelium, makes the kidney particularly vulnerable to drug-induced injury. However, the development of drugs with improved renal safety has proven to be challenging, because many current medical studies still rely on traditional two-dimensional (2D) in vitro cell culture or animal models for drug testing and toxicity assays. However, these two models have insurmountable shortcomings.
Kidney organoid is a promising tool for drug nephrotoxicity testing, and construction of the kidney organoids fills the gap between currently accepted in vitro cell culture models and in vivo functional analysis. In addition, the use of organoids should reduce the reliance on experimental animals.
Organoids have the ability to respond to drugs and toxins in almost the same way as actual human organs, and as such, can more accurately predict drug efficacy and safety in humans. In addition, the recent advances in cell culture technology, stem cell biology, biomaterials, and microfluidics have been applied to the development of human organoids and human organs-on-a-chip (micro-physiological systems), offering the potential to provide better in vitro models to perform toxicological studies by more closely modeling the in vivo environment.
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