Are some animal models more equal than others? A case study on the translational value of animal models of efficacy for Alzheimer's disease.

Autor: Veening-Griffioen DH; Utrecht Institute of Pharmaceutical Sciences, Department of Pharmaceutics, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, the Netherlands. Electronic address: d.h.veening-griffioen@uu.nl., Ferreira GS; Utrecht Institute of Pharmaceutical Sciences, Department of Pharmaceutics, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, the Netherlands., van Meer PJK; Utrecht Institute of Pharmaceutical Sciences, Department of Pharmaceutics, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, the Netherlands; Medicines Evaluation Board, Graadt van Roggenweg 500, 3531 AH, Utrecht, the Netherlands., Boon WPC; Copernicus Institute of Sustainable Development, Innovation Studies, Utrecht University, Princetonlaan 8a, 3584 CB, Utrecht, the Netherlands., Gispen-de Wied CC; Medicines Evaluation Board, Graadt van Roggenweg 500, 3531 AH, Utrecht, the Netherlands., Moors EHM; Copernicus Institute of Sustainable Development, Innovation Studies, Utrecht University, Princetonlaan 8a, 3584 CB, Utrecht, the Netherlands., Schellekens H; Utrecht Institute of Pharmaceutical Sciences, Department of Pharmaceutics, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, the Netherlands.
Jazyk: angličtina
Zdroj: European journal of pharmacology [Eur J Pharmacol] 2019 Sep 15; Vol. 859, pp. 172524. Date of Electronic Publication: 2019 Jul 07.
DOI: 10.1016/j.ejphar.2019.172524
Abstrakt: Clinical trial failures (>99%) in Alzheimer's disease are in stark contrast to positive efficacy data in animals. We evaluated the correlation between animal and clinical efficacy outcomes (cognition) in Alzheimer's disease using data from registered drugs as well as interventions tested in phase II or III clinical trials for Alzheimer's disease. We identified 20 interventions, which were tested in 208 animal studies in 63 different animal models. Clinical outcome was correlated with animal results in 58% of cases. But, individual animal models showed divergent results across interventions, individual interventions showed divergent results across animal models, and animal model outcomes were determined with 16 different methods. This result is unsurprising due to poor external validity (what do we model) of the animal models. Although the animal models all share Alzheimer's disease symptoms, none represents the whole syndrome. Investigators did not motivate why one model was chosen over another, and did not consider the ways the disease phenomena were generated (spontaneous, (experimentally) induced or by genetic modification), or the species characteristics, which determine the outcomes. The explanation for the lack of correlation between animal and human outcomes can be manifold: the pathogenesis of Alzheimer's disease is not reflected in the animal model or the outcomes are not comparable. Our conclusion is that currently no animal models exist which are predictive for the efficacy of interventions for Alzheimer's disease.
(Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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