One Size Fits All?: Ethical Considerations for Examining Efficacy in First-in-Human Pluripotent Stem Cell Studies

Habets, Michelle G J L; Delden, Johannes J. M. van; Niemansburg, Sophie L.; Atkins, Harold L.; Bredenoord, Annelien L.

doi:10.1038/mt.2016.202

Cited by 4 publications

(1 citation statement)

References 30 publications

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“…The process of drug development itself may be profoundly changed by organoids technology; nowadays, Phase I clinical trials are aimed to determine the maximum tolerated dose of a novel drug molecule, while efficacy is evaluated in Phase II and III trials. Future early clinical-like studies to be performed in organoids may combine safety and efficacy determination [9], specifically targeting tumor cells while leaving healthy cells unharmed, resulting in reduced toxicities in patients. Hepatic organoid cultures provide a relevant model for preclinical testing of the hepatotoxicity of experimental compounds [10], while cardiac organoids can be used for testing cardiotoxicity [11], and kidney organoids have been used for toxicological studies [12].…”

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Use of Organoids in Medicinal Chemistry: Challenges on Ethics and Biosecurity

Rinaldi

Colotti

2019

Future Med. Chem.

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Organoids: applicationsOrganoids are three-dimensional (3D) multicellular stem-cell-derived systems comprising organ-specific cell types, that exhibit key structural and functional properties of a variety of specific organs [1]; this technology has been chosen by Nature Methods as Method of the Year 2017 for the fascinating potential as tool to probe human biology and disease.Organoids can be grown from pluripotent stem cells, embryonic stem cells, induced pluripotent stem cells and from organ-restricted adult stem cells. These cells differentiate in a controlled fashion in specific growth factors and culture media, with the support of a 3D matrix which allows cell growth, orientation and stratification. The resulting organoids replicate the development, metabolism, architecture and physiology of the real organ [2]. In fact, unlike in vitro traditional 2D cultures, organoids are formed by genomic stable, self-renewing and self-organizing stem cell-derived populations of differentiated cells that exhibit similar composition (they comprise all major cell lineages at frequencies similar to those in living tissue) and similar organ architecture and functionality as the tissue of origin. The technique allows expansions of tissue-specific stem cells and their differentiated progeny. Starting from very small amounts of material (such as biopsies); organoids can be expanded indefinitely, cryopreserved as biobanks and easily manipulated using techniques similar to those used for traditional 2D cell cultures [3]. Organoids are of course more physiologically relevant than traditional cell culture models and are easier to manipulate and study than in vivo mouse/human models. Gene-editing technologies can be used to produce and even self-transplant repaired, healthy organoids from patients with genetic defects.In the last years, human organoids have been established for a wide range of organs, including salivary gland, esophagus, stomach, pancreas, liver, intestine, colon, kidney, prostate, lung, retina and brain. Using organoids, many types of human diseases have been modeled, ranging from Barrett's esophagus to Helicobacter pylori infection, cystic fibrosis, inflammatory bowel disease, bacterial or viral infections and even autism [3]. The luminal epithelia of human gastric organoids are efficiently colonized by Helicobacter pylori (the bacterium identified as the major cause of gastritis and one of the major agents of gastric cancer onset) and relevant physiological changes were demonstrated in this setting, including an increase in proliferation due to oncogenic CagA and increased β-catenin signaling [4]. Further, renal organoids have been used for the study of infections caused by Shiga-toxin-producing Escherichia coli [5]; these types of studies are yielding important contributions in understanding the pathogenic mechanisms of infections and are used to improve the strategies of treatment.Many cancer models have been studied using organoids from glioblastoma, colorectal, gastrointestinal, pancreatic, prostate, breast, b...

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confidence: 99%