Can Animal Models of Disease Reliably Inform Human Studies?

Worp, H. Bart van der; Howells, David W.; Sena, Emily S.; Porritt, Michelle J.; Rewell, Sarah S J; O’Collins, Victoria; Macleod, Malcolm

doi:10.1371/journal.pmed.1000245

Cited by 1,101 publications

(841 citation statements)

References 51 publications

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“…The few examples of portal hypertension in vitro studies in the literature are based on rat hepatectomy [16] or are focused on understanding the correlations between endothelial dysfunction and liver diseases [17]. However, in many instances animal models are not sufficiently predictive of human pathophysiology [18]. Moreover, as far as in vitro methods are concerned, traditional incubators cannot be used to provide pressure variations typical of those observed in portal hypertension.…”

Section: Introductionmentioning

confidence: 99%

Environmental Control in Flow Bioreactors

et al. 2017

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Abstract:The realization of physiologically-relevant advanced in vitro models is not just related to the reproduction of a three-dimensional multicellular architecture, but also to the maintenance of a cell culture environment in which parameters, such as temperature, pH, and hydrostatic pressure are finely controlled. Tunable and reproducible culture conditions are crucial for the study of environment-sensitive cells, and can also be used for mimicking pathophysiological conditions related with alterations of temperature, pressure and pH. Here, we present the SUITE (Supervising Unit for In Vitro Testing) system, a platform able to monitor and adjust local environmental variables in dynamic cell culture experiments. The physical core of the control system is a mixing chamber, which can be connected to different bioreactors and acts as a media reservoir equipped with a pH meter and pressure sensors. The chamber is heated by external resistive elements and the temperature is controlled using a thermistor. A purpose-built electronic control unit gathers all data from the sensors and controls the pH and hydrostatic pressure by regulating air and CO 2 overpressure and flux. The system's modularity and the possibility of imposing different pressure conditions were used to implement a model of portal hypertension with both endothelial and hepatic cells. The results show that the SUITE platform is able to control and maintain cell culture parameters at fixed values that represent either physiological or pathological conditions. Thus, it represents a fundamental tool for the design of biomimetic in vitro models, with applications in disease modelling or toxicity testing.

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Section: Introductionmentioning

confidence: 99%

Environmental Control in Flow Bioreactors

et al. 2017

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“…However, as is the case in many areas of biomedical research, the promising results from preclinical animal models have failed to be translated effectively into the clinic 13, 14, 15. This is exemplified by two unsuccessful phase III randomized controlled trials of gene therapy16, 17 and variable responses in other smaller clinical studies 6, 18, 19, 20, 21…”

Section: Introductionmentioning

confidence: 99%

A systematic review and meta‐analysis of gene therapy in animal models of cerebral glioma: why did promise not translate to human therapy?

Hirst

Vesterinen

Conlin

et al. 2014

Evid Based Preclin Med

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BackgroundThe development of therapeutics is often characterized by promising animal research that fails to translate into clinical efficacy; this holds for the development of gene therapy in glioma. We tested the hypothesis that this is because of limitations in the internal and external validity of studies reporting the use of gene therapy in experimental glioma.MethodWe systematically identified studies testing gene therapy in rodent glioma models by searching three online databases. The number of animals treated and median survival were extracted and studies graded using a quality checklist. We calculated median survival ratios and used random effects meta‐analysis to estimate efficacy. We explored effects of study design and quality and searched for evidence of publication bias.ResultsWe identified 193 publications using gene therapy in experimental glioma, including 6,366 animals. Overall, gene therapy improved median survival by a factor of 1.60 (95% CI 1.53–1.67). Study quality was low and the type of gene therapy did not account for differences in outcome. Study design characteristics accounted for a significant proportion of between‐study heterogeneity. We observed similar findings in a data subset limited to the most common gene therapy.ConclusionAs the dysregulation of key molecular pathways is characteristic of gliomas, gene therapy remains a promising treatment for glioma. Nevertheless, we have identified areas for improvement in conduct and reporting of studies, and we provide a basis for sample size calculations. Further work should focus on genes of interest in paradigms recapitulating human disease. This might improve the translation of such therapies into the clinic.

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“…of animal models (and their implementation) used in preclinical studies 12 . I have previously argued that a major problem with the status quo in preclinical pain research is the animal models in common use; the inadequacies are related to all three facets of an animal model: subjects, assays, and measures 13 .…”

Section: Jeffrey S Mogilmentioning

confidence: 99%