Translation of Research Evidence From Animals to Humans

Hackam, Daniel G.; Redelmeier, Donald A.

doi:10.1001/jama.296.14.1731

Cited by 614 publications

(477 citation statements)

References 4 publications

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“…However, few of these human trials have shown success (4)(5)(6)(7). The success rate is even worse for those trials in the field of inflammation, a condition present in many human diseases.…”

mentioning

confidence: 99%

Genomic responses in mouse models poorly mimic human inflammatory diseases

Seok

Warren²,

Cuenca

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

2,590

1,921

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A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R 2 between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases.human disease | translational medicine | inflammation | immune response | injury M urine models have been extensively used in recent decades to identify and test drug candidates for subsequent human trials (1-3). However, few of these human trials have shown success (4-7). The success rate is even worse for those trials in the field of inflammation, a condition present in many human diseases. To date, there have been nearly 150 clinical trials testing candidate agents intended to block the inflammatory response in critically ill patients, and every one of these trials failed (8-11). Despite commentaries that question the merit of an overreliance of animal systems to model human immunology (3,12,13), in the absence of systematic evidence, investigators and public regulators assume that results from animal research reflect human disease. To date, there have been no studies to systematically evaluate, on a molecular basis, how well the murine clinical models mimic human inflammatory diseases in patients.The Inflammation and Host Response to Injury, Large Scale Collaborative Research Program has completed multiple studies on the genomic responses to systemic inflammation in patients and human volunteers as well as murine models (14-18). These datasets include genome-wide expression analysis on white blood cells obtained from serial blood draws in 167 patients up to 28 d after severe blunt trauma (15), 244 patients up to 1 y after burn injury, and 4 healthy humans for 24 h after administration of low-dose bacterial endotoxin (14) and expression analysis on analogous samples from well-established mouse models of trauma, burns, and endotoxemia (16 treated and 16 controls per model) (16-18). In humans, severe inflammatory stress produces a genomic storm affecting all major cellular functions and pathways (15) and therefore, provided sufficient perturbations to allow comparisons between the genes in the human conditions and their orthologs in the murine models.In this article, we report on a systematic comparison of the genomic respo...

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mentioning

confidence: 99%

Genomic responses in mouse models poorly mimic human inflammatory diseases

Seok

Warren²,

Cuenca

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

2,590

1,921

View full text Add to dashboard Cite

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“…[18][19][20][21][22] This problem has been highlighted by a number of recent, high-profile commentaries from the pharmaceutical industry, 18,19,23 funding agencies, including the National Institutes of Health, 24,25 scientific journals, 26,27 veterinarians, 28 academics, and biostatisticians. [29][30][31][32][33][34][35][36] This is of particular importance when animal models are used to advance the development of clinical therapeutics. Not only does this level of uncertainty potentially waste millions of funding dollars, 37 but there are also genuine ethical concerns regarding the clinical evaluation of agents with supporting rationale that is solely on the basis of experimental evidence derived from studies in animal models.…”

Section: Common Concerns About Preclinical Study Design and Reportingmentioning

confidence: 99%

Bridging Translation by Improving Preclinical Study Design in AKI

Caestecker

Humphreys

Liu

et al. 2015

Journal of the American Society of Nephrology

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Despite extensive research, no therapeutic interventions have been shown to prevent AKI, accelerate recovery of AKI, or reduce progression of AKI to CKD in patients. This failure in translation has led investigators to speculate that the animal models being used do not predict therapeutic responses in humans. Although this issue continues to be debated, an important concern that has not been addressed is whether improvements in preclinical study design can be identified that might also increase the likelihood of translating basic AKI research into clinical practice using the current models. In this review, we have taken an evidence-based approach to identify common weaknesses in study design and reporting in preclinical AKI research that may contribute to the poor translatability of the findings. We focused on use of N-acetylcysteine or sodium bicarbonate for the prevention of contrastinduced AKI and use of erythropoietin for the prevention of AKI, two therapeutic approaches that have been extensively studied in clinical trials. On the basis of our findings, we identified five areas for improvement in preclinical study design and reporting. These suggested and preliminary guidelines may help improve the quality of preclinical research for AKI drug development.

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“…This has limited the translation of the target to the clinic [4]. Screening systems using different species, such as worm, fruit fly, and zebrafish, have proven extremely useful for basic science insights and, on occasion, repurposing previously approved drugs from the Food and Drug…”

Section: Limitations With Current Cns Modelsmentioning

confidence: 99%

“…Equally important, these models should enable the investigation of genetic and environmental risk factors contributing to diseases in a rapid and economical way. Currently used models often do not reflect a typical human response [2][3][4], despite efforts underway to better characterize these models and increase their preclinical value in predicting safety and efficacy in the clinic [5,6]. Therefore, there is a great need to develop disease-and patient-specific models from cells directly affected in CNS disorders.…”

mentioning

confidence: 99%

Induced Pluripotent Stem Cell Models to Enable In Vitro Models for Screening in the Central Nervous System

Hunsberger

Efthymiou

Malik

et al. 2015

Stem Cells and Development

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There is great need to develop more predictive drug discovery tools to identify new therapies to treat diseases of the central nervous system (CNS). Current nonpluripotent stem cell-based models often utilize non-CNS immortalized cell lines and do not enable the development of personalized models of disease. In this review, we discuss why in vitro models are necessary for translational research and outline the unique advantages of induced pluripotent stem cell (iPSC)-based models over those of current systems. We suggest that iPSC-based models can be patient specific and isogenic lines can be differentiated into many neural cell types for detailed comparisons. iPSC-derived cells can be combined to form small organoids, or large panels of lines can be developed that enable new forms of analysis. iPSC and embryonic stem cell-derived cells can be readily engineered to develop reporters for lineage studies or mechanism of action experiments further extending the utility of iPSC-based systems. We conclude by describing novel technologies that include strategies for the development of diversity panels, novel genomic engineering tools, new three-dimensional organoid systems, and modified high-content screens that may bring toxicology into the 21st century. The strategic integration of these technologies with the advantages of iPSC-derived cell technology, we believe, will be a paradigm shift for toxicology and drug discovery efforts.Disease Modeling D iseases of the central nervous system (CNS) affect a large number of people, but therapeutic intervention is hampered by the lack of useful models for many of these diseases. Current research on human subjects, particularly for drug discovery for CNS diseases, is severely (and appropriately) limited by ethical guidelines. Therefore, surrogate models are needed that share important anatomical, physiological, and genetic features to advance new treatments and therapies for CNS diseases [1].Developing rapid and effective therapies for CNS diseases requires the availability of in vitro models that accurately recapitulate disease phenotypes and predict patient treatment response. A proper model must be both sensitive and predictive while reflecting both normal and disease processes. Equally important, these models should enable the investigation of genetic and environmental risk factors contributing to diseases in a rapid and economical way. Currently used models often do not reflect a typical human response [2-4], despite efforts underway to better characterize these models and increase their preclinical value in predicting safety and efficacy in the clinic [5,6]. Therefore, there is a great need to develop disease-and patient-specific models from cells directly affected in CNS disorders. These cellbased models, we envision, could either replace or supplement current animal models and enable the efficient translation of basic research into the clinical setting. Limitations with current CNS modelsCurrently, drug discovery relies on the use of animalbased or cell-based models, ...

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Translation of Research Evidence From Animals to Humans

Cited by 614 publications

References 4 publications

Genomic responses in mouse models poorly mimic human inflammatory diseases

Genomic responses in mouse models poorly mimic human inflammatory diseases

Bridging Translation by Improving Preclinical Study Design in AKI

Induced Pluripotent Stem Cell Models to Enable In Vitro Models for Screening in the Central Nervous System

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