Recent efforts to elucidate the scientific validity of animal-based drug tests by the pharmaceutical industry, pro-testing lobby groups, and animal welfare organisations

Bailey, Jarrod; Balls, Michael

doi:10.1186/s12910-019-0352-3

Cited by 44 publications

(39 citation statements)

References 40 publications

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“…For example, infectious diseases have been studied in non-human primates in the past. However, besides the ethical aspects it is also important to keep in mind that conservation of gene functions, molecular processes, and physiological regulations with the human context is not guaranteed [ 17 , 18 , 19 , 20 ].…”

Section: Animal Models and Immortalized 2d Human Cell Culture Modementioning

confidence: 99%

Human Embryo Models and Drug Discovery

Rosner¹,

Reithofer²,

Fink³

et al. 2021

IJMS

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For obvious reasons, such as, e.g., ethical concerns or sample accessibility, model systems are of highest importance to study the underlying molecular mechanisms of human maladies with the aim to develop innovative and effective therapeutic strategies. Since many years, animal models and highly proliferative transformed cell lines are successfully used for disease modelling, drug discovery, target validation, and preclinical testing. Still, species-specific differences regarding genetics and physiology and the limited suitability of immortalized cell lines to draw conclusions on normal human cells or specific cell types, are undeniable shortcomings. The progress in human pluripotent stem cell research now allows the growth of a virtually limitless supply of normal and DNA-edited human cells, which can be differentiated into various specific cell types. However, cells in the human body never fulfill their functions in mono-lineage isolation and diseases always develop in complex multicellular ecosystems. The recent advances in stem cell-based 3D organoid technologies allow a more accurate in vitro recapitulation of human pathologies. Embryoids are a specific type of such multicellular structures that do not only mimic a single organ or tissue, but the entire human conceptus or at least relevant components of it. Here we briefly describe the currently existing in vitro human embryo models and discuss their putative future relevance for disease modelling and drug discovery.

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Section: Animal Models and Immortalized 2d Human Cell Culture Modementioning

confidence: 99%

Human Embryo Models and Drug Discovery

Rosner¹,

Reithofer²,

Fink³

et al. 2021

IJMS

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“…Provided that studies are perfectly designed, employ optimal models and are conducted meticulously, what is the level of concordance that society and scientists are willing to accept? This lack of standardisation leads to the extraordinary situation of both proponents and opponents of the current animal research paradigm citing the same data to defend their arguments [41,62,63].…”

Section: Levelling the Translational Gap For Animal To Human Efficacymentioning

confidence: 99%

Levelling the Translational Gap for Animal to Human Efficacy Data

Ferreira

Veening-Griffioen

Boon

et al. 2020

Animals

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Reports of a reproducibility crisis combined with a high attrition rate in the pharmaceutical industry have put animal research increasingly under scrutiny in the past decade. Many researchers and the general public now question whether there is still a justification for conducting animal studies. While criticism of the current modus operandi in preclinical research is certainly warranted, the data on which these discussions are based are often unreliable. Several initiatives to address the internal validity and reporting quality of animal studies (e.g., Animals in Research: Reporting In Vivo Experiments (ARRIVE) and Planning Research and Experimental Procedures on Animals: Recommendations for Excellence (PREPARE) guidelines) have been introduced but seldom implemented. As for external validity, progress has been virtually absent. Nonetheless, the selection of optimal animal models of disease may prevent the conducting of clinical trials, based on unreliable preclinical data. Here, we discuss three contributions to tackle the evaluation of the predictive value of animal models of disease themselves. First, we developed the Framework to Identify Models of Disease (FIMD), the first step to standardise the assessment, validation and comparison of disease models. FIMD allows the identification of which aspects of the human disease are replicated in the animals, facilitating the selection of disease models more likely to predict human response. Second, we show an example of how systematic reviews and meta-analyses can provide another strategy to discriminate between disease models quantitatively. Third, we explore whether external validity is a factor in animal model selection in the Investigator’s Brochure (IB), and we use the IB-derisk tool to integrate preclinical pharmacokinetic and pharmacodynamic data in early clinical development. Through these contributions, we show how we can address external validity to evaluate the translatability and scientific value of animal models in drug development. However, while these methods have potential, it is the extent of their adoption by the scientific community that will define their impact. By promoting and adopting high quality study design and reporting, as well as a thorough assessment of the translatability of drug efficacy of animal models of disease, we will have robust data to challenge and improve the current animal research paradigm.

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“…Thirdly, the toxicity or the lack of certain molecules or chemicals in animals is not always reflected in humans. Analyses done by Baily and colleagues comparing drug responses between preclinical species (dog, rat, mouse, rabbit, and non-human primates) and man showed that the absence of toxicity in animal species was not predictive of an absence of adverse drug reactions in humans (Bailey et al, 2014(Bailey et al, , 2015Bailey and Balls, 2019). For instance, vancomycin, often used as a last resort antibiotic against multi-drug-resistant Grampositive bacteria, can cause hypersensitivity reactions such as the Red Man Syndrome and anaphylaxis, but these are only observed in man (Sivagnanam and Deleu, 2003).…”

Section: Limitations Of Using In Vivo Animal Models For Drug Discoverymentioning

confidence: 99%

Utilizing Organoid and Air-Liquid Interface Models as a Screening Method in the Development of New Host Defense Peptides

Choi

Lee

et al. 2020

Front. Cell. Infect. Microbiol.

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Host defense peptides (HDPs), also known as antimicrobial peptides, are naturally occurring polypeptides (∼12-50 residues) composed of cationic and hydrophobic amino acids that adopt an amphipathic conformation upon folding usually after contact with membranes. HDPs have a variety of biological activities including immunomodulatory, anti-inflammatory, anti-bacterial, and anti-biofilm functions. Although HDPs have the potential to address the global threat of antibiotic resistance and to treat immune and inflammatory disorders, they have yet to achieve this promise. Indeed, there are several challenges associated with bringing peptide-based drug candidates from the lab bench to clinical practice, including identifying appropriate indications, stability, toxicity, and cost. These challenges can be addressed in part by the development of innate defense regulator (IDR) peptides and peptidomimetics, which are synthetic derivatives of HDPs with similar or better efficacy, increased stability, and reduced toxicity and cost of the original HDP. However, one of the largest gaps between basic research and clinical application is the validity and translatability of conventional model systems, such as cell lines and animal models, for screening HDPs and their derivatives as potential drug therapies. Indeed, such translation has often relied on animal models, which have only limited validity. Here we discuss the recent development of human organoids for disease modeling and drug screening, assisted by the use of omics analyses. Organoids, developed from primary cells, cell lines, or human pluripotent stem cells, are three-dimensional, self-organizing structures that closely resemble their corresponding in vivo organs with regards to immune responses, tissue organization, and physiological properties; thus, organoids represent a reliable method for studying efficacy, formulation, toxicity and to some extent drug stability and pharmacodynamics. The use of patient-derived organoids enables the study of patient-specific efficacy, toxicogenomics and drug response predictions. We outline how organoids and omics data analysis can be leveraged to aid in the clinical translation of IDR peptides.

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Recent efforts to elucidate the scientific validity of animal-based drug tests by the pharmaceutical industry, pro-testing lobby groups, and animal welfare organisations

Cited by 44 publications

References 40 publications

Human Embryo Models and Drug Discovery

Human Embryo Models and Drug Discovery

Levelling the Translational Gap for Animal to Human Efficacy Data

Utilizing Organoid and Air-Liquid Interface Models as a Screening Method in the Development of New Host Defense Peptides

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