This project aims to develop a frog embryo toxicology assay which in combination with tests on organ-specific mammalian cell lines and in silico modelling can be used to predict the toxicity of drugs in early development.
The development of new methods to predict toxicity of drugs is important in screening out hazardous compounds that would subsequently fail in safety testing in animals. Xenopus embryos have long been used in the Frog Embryo Teratogenesis Assay Xenopus (FETAX) toxicity test and the proposal to modify the test for toxicology testing (FETOX – the Frog Embryo Toxicology assay) offers the possibility of a predictive test for use in early preclinical development. This could prevent toxic compounds advancing into large scale regulatory toxicology studies in animals.
Research details and methods
The model will be developed using frog embryos at different stages of development related to organogenesis and establishment of the vasculature, thereby testing both teratogenesis and general toxicity. Standard compounds with well-characterised organ-specific toxicities will be tested to generate disposition and toxicity benchmarks. These will be used to create a toxicity index that can be validated against historic toxicity data generated from animal tests.
Currently protocols to assess the safety of new drugs use mammalian models to predict the potential toxicity of novel compounds. Incorporating mammals as models in these early toxicity assessment protocols is undesirable due to cost effectiveness and the need to reduce mammalian testing in drug development. We propose to create a preclinical drug development protocol to predict the potential toxicity of new compounds integrating computer modeling, in vitro methodologies and in vivo assessment using larval forms of the amphibian, Xenopus laevis. Xenopus has long been used as a teratogenic screening model in the Frog Embryo Teratogenesis Assay Xenopus (FETAX) toxicity screening test. We plan to modify the FETAX assay to look at toxicity as well as teratogenicity. The new assay we term FETOX (Frog Embryo TOXicology assay). This assay will be used for predicting toxicity of drugs and will be combined with multi-parametric analysis on selected cell lines (related to the organs with predicted toxicity) and in silico modelling that will allow a hazard assessment decisions to be made prior to further research in mammalian models. This exciting prospect aims to fill a current gap between cytotoxicity assessment and systemic toxicity in a whole organism without the need for mammalian models in the early stages of drug development.
González-Paredes A et al. (2019). Solid lipid nanoparticles for the delivery of anti-microbial oligonucleotides. Eur J Pharm Biopharm 134:166-77. doi: 10.1016/j.ejpb.2018.11.017
Saide K et al. (2019). Paracetamol-induced liver injury modelled in Xenopus laevis embryos. Toxicology Letters 302:83-91. doi: 10.1016/j.toxlet.2018.09.016
Marín-Barba M et al. (2018). Unravelling the mechanisms that determine the uptake and metabolism of magnetic single and multicore nanoparticles in a Xenopus laevis model. Nanoscale 10(2):690-704. doi: 10.1039/c7nr06020c
Al-Yousuf K et al. (2017). Combining Cytotoxicity Assessment and Xenopus laevis Phenotypic Abnormality Assay as a Predictor of Nanomaterial Safety. Current Protocols in Toxicology 73:20.13.1-20.13.33. doi: 10.1002/cptx.25
Mamusa M et al. (2017). Cationic liposomal vectors incorporating a bolaamphiphile for oligonucleotide antimicrobials. Biochimica et Biophysica acta. Biomembranes 1859(10):1767-1777. doi: 10.1016/j.bbamem.2017.06.006
Webster CA et al. (2016). An early developmental vertebrate model for nanomaterial safety: bridging cell-based and mammalian toxicity assessment. Nanomedicine (London, England) 11(6):643-56. doi: 10.2217/nnm.15.219
Principal investigatorDr Grant Wheeler
InstitutionUniversity of East Anglia
Co-InvestigatorDr Vicky Sherwood
Dr Dominic Williams