Accelerating drug discovery for Alzheimer's disease: best practices for preclinical animal studies

Abstract

Animal models have contributed significantly to our understanding of the underlying biological mechanisms of Alzheimer's disease (AD). As a result, over 300 interventions have been investigated and reported to mitigate pathological phenotypes or improve behavior in AD animal models or both. To date, however, very few of these findings have resulted in target validation in humans or successful translation to disease-modifying therapies. Challenges in translating preclinical studies to clinical trials include the inability of animal models to recapitulate the human disease, variations in breeding and colony maintenance, lack of standards in design, conduct and analysis of animal trials, and publication bias due to under-reporting of negative results in the scientific literature. The quality of animal model research on novel therapeutics can be improved by bringing the rigor of human clinical trials to animal studies. Research communities in several disease areas have developed recommendations for the conduct and reporting of preclinical studies in order to increase their validity, reproducibility, and predictive value. To address these issues in the AD community, the Alzheimer's Drug Discovery Foundation partnered with Charles River Discovery Services (Morrisville, NC, USA) and Cerebricon Ltd. (Kuopio, Finland) to convene an expert advisory panel of academic, industry, and government scientists to make recommendations on best practices for animal studies testing investigational AD therapies. The panel produced recommendations regarding the measurement, analysis, and reporting of relevant AD targets, th choice of animal model, quality control measures for breeding and colony maintenance, and preclinical animal study design. Major considerations to incorporate into preclinical study design include a priori hypotheses, pharmacokinetics-pharmacodynamics studies prior to proof-of-concept testing, biomarker measurements, sample size determination, and power analysis. The panel also recommended distinguishing between pilot 'exploratory' animal studies and more extensive 'therapeutic' studies to guide interpretation. Finally, the panel proposed infrastructure and resource development, such as the establishment of a public data repository in which both positive animal studies and negative ones could be reported. By promoting best practices, these recommendations can improve the methodological quality and predictive value of AD animal studies and make the translation to human clinical trials more efficient and reliable.

Translating the Science of Aging into Therapeutic Interventions

“…This approach has drawbacks for drug development. Single-gene mutations that lead to AD-like phenotypes in young animals do not fully mimic human AD in older patients (Shineman et al 2011). Animals in which dysfunction-provoking mutations can be induced in later life could be better models for drug development, because an aging tissue microenvironment would exist.…”

Best Practices and Standard Protocols as a Tool to Enhance Translation for Neuromuscular Disorders

“…The problematic of bench research delivering efficacy data that turn out not to show any efficacy in patient studies is not new and was discussed thoroughly in the communities of both rare and common diseases [1,5,6,[9][10][11]. A general problem that makes it difficult to compare these studies and draw conclusions is the incomplete reporting of experimental settings or data generation.…”

“…In addition to transparency in reporting, animalspecific best practices that take account of bias related to a specific animal model should be considered: this issue was addressed for mouse models of Duchenne Muscular Dystrophy [15] [5,16] and also for other, non neuromuscular diseases [10,11]. Comparing recommendations suggested by the different authors [15,[17][18][19] and guidelines adopted by single institutions (see for instance http://www.nih.gov/about/ reporting-preclinical-research.htm, based on [6]), it seems that some general rules of transparency should apply to all confirmatory preclinical studies, independently of the disease addressed.…”

The Future of Preclinical Animal Models in Pharmaceutical Discovery and Development

“…There are many potential sources of bias to be considered across all study phases ranging from design to interpretation (Lindner 2007). In a number of therapeutic areas, there are best practices that are being formulated to advance the translational value of preclinical studies, and undoubtedly this effort will continue and accelerate (E. Sena et al 2007;Scott et al 2008;Shineman et al 2011). …”