Alzheimer's therapeutics: Translation of preclinical science to clinical drug development

Alena V. Savonenko, Tatiana Melnikova, Andrew Hiatt, Tong Li, Paul F. Worley, Juan C. Troncoso, Phil C. Wong, Don L. Price

Research output: Contribution to journalReview article

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 translationfrom 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.

Original languageEnglish (US)
Pages (from-to)261-277
Number of pages17
JournalNeuropsychopharmacology
Volume37
Issue number1
DOIs
StatePublished - Jan 1 2012

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Keywords

  • acetylcholinesterase inhibitors
  • amyloid cascade
  • animal models
  • anti-Ab immunization
  • g-secretase inhibition
  • neurodegeneration

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

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