Alzheimer's Therapeutics: Translation of Preclinical Science to Clinical Drug Development |
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| Authors: | Alena V Savonenko Tatiana Melnikova Andrew Hiatt Tong Li Paul F Worley Juan C Troncoso Phil C Wong Don L Price |
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| Affiliation: | 1.Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA;2.Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA;3.MAPP Biopharmaceutical, San Diego, CA, USA;4.Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA |
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| Abstract: | Over the past three decades, significant progress has been made in understanding the neurobiology of Alzheimer''s disease. In recent years, the first attempts to implement novel mechanism-based treatments brought rather disappointing results, with low, if any, drug efficacy and significant side effects. A discrepancy between our expectations based on preclinical models and the results of clinical trials calls for a revision of our theoretical views and questions every stage of translation—from how we model the disease to how we run clinical trials. In the following sections, we will use some specific examples of the therapeutics from acetylcholinesterase inhibitors to recent anti-Aβ immunization and γ-secretase inhibition to discuss whether preclinical studies could predict the limitations in efficacy and side effects that we were so disappointed to observe in recent clinical trials. We discuss ways to improve both the predictive validity of mouse models and the translation of knowledge between preclinical and clinical stages of drug development. |
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| Keywords: | animal models, neurodegeneration, γ -secretase inhibition, amyloid cascade, anti-Aβ immunization, acetylcholinesterase inhibitors |
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