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Review

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

Diana W Shineman1*, Guriqbal S Basi2, Jennifer L Bizon3, Carol A Colton4, Barry D Greenberg5, Beth A Hollister6, John Lincecum7, Gabrielle G Leblanc8, Linda (Bobbi) H Lee19, Feng Luo10, Dave Morgan11, Iva Morse12, Lorenzo M Refolo13, David R Riddell14, Kimberly Scearce-Levie15, Patrick Sweeney16, Juha Yrjänheikki16 and Howard M Fillit1

Author Affiliations

1 Alzheimer's Drug Discovery Foundation, 57 West 57 Street, Suite 904, New York, NY 10019, USA

2 Elan Pharmaceuticals, 1000 Gateway Boulevard, South San Francisco, CA 94080, USA

3 Evelyn F. and William L. McKnight Brain Institute, University of Florida, 100 S. Newell Drive, Gainesville, FL 32610-0244, USA

4 Duke University Medical Center, 201H Bryan Research Building, Research Drive, Durham, NC 27710, USA

5 University Health Network, Toronto Western Research Institute, 399 Bathurst Street, MP 14-328, Toronto, ON, M5T 2S8, Canada

6 Charles River Discovery Services, 3300 Gateway Centre Boulevard, Morrisville, NC 27560, USA

7 ALS Therapy Development Institute, 215 First Street, Cambridge, MA 02142, USA

8 Leblanc Neuroscience Consulting, 960 Miller Avenue, Berkeley, CA 94708, USA

9 Columbia University, 630 West 168th Street, Building PS 12-510, New York, NY 10032, USA

10 Abbott Neuroscience, AP4-2, 100 Abbott Park Road, Abbott Park, IL 60064-6076, USA

11 USF Health Byrd Alzheimer Institute, University of South Florida, 4001 E. Fletcher Avenue, MDC Box 36, Tampa FL 33613, USA

12 Genetically Engineered Models and Services/Charles River Laboratories, Inc., 251 Ballardvale Street, Wilmington, MA 01887, USA

13 National Institute on Aging, 7201 Wisconsin Avenue, Gateway Building, Suite 350, Bethesda, MD 20892, USA

14 Pfizer Neuroscience Research Unit, MS 8220-3414, Eastern Point Road, Groton, CT 06340, USA

15 Genentech, 1 DNA Way, South San Francisco, CA 94080, USA

16 Cerebricon Ltd./Charles River Discovery Services, Microkatu 1, Kuopio, Finland 70210

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Alzheimer's Research & Therapy 2011, 3:28  doi:10.1186/alzrt90

Published: 28 September 2011

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.