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

doi:10.1038/npp.2011.211

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

School of Medicine

Research output: Contribution to journal › Review article › peer-review

39 Scopus citations

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 language	English (US)
Pages (from-to)	261-277
Number of pages	17
Journal	Neuropsychopharmacology
Volume	37
Issue number	1
DOIs	https://doi.org/10.1038/npp.2011.211
State	Published - Jan 2012

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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title = "Alzheimer's therapeutics: Translation of preclinical science to clinical drug development",

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.",

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author = "Savonenko, {Alena V.} and Tatiana Melnikova and Andrew Hiatt and Tong Li and Worley, {Paul F.} and Troncoso, {Juan C.} and Wong, {Phil C.} and Price, {Don L.}",

note = "Funding Information: We thank our many colleagues at JHMI and other institutions who have contributed to the original work cited in this review and have engaged us in helpful discussions. We are grateful to Dr A Huberman for careful editing and discussion of the manuscript. Owing to space constrains we were unable to cite all studies relevant to topics discussed. Aspects of this work were supported by grants from the US Public Health Service (NS45150, NS47308, NS41438, NS49088, NS10580, AG05146, AG14248, MH086881, NS047225, and TW008019), as well as the Metropolitan Life Foundation, Adler Foundation, Alzheimer{\textquoteright}s Association, American Health Assistance Foundation, Rotary CART Fund, Wallace Foundation, Ellison Medical Foundation, and Bristol-Myers Squibb Foundation.",

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AU - Savonenko, Alena V.

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AU - Hiatt, Andrew

AU - Li, Tong

AU - Worley, Paul F.

AU - Troncoso, Juan C.

AU - Wong, Phil C.

AU - Price, Don L.

N1 - Funding Information: We thank our many colleagues at JHMI and other institutions who have contributed to the original work cited in this review and have engaged us in helpful discussions. We are grateful to Dr A Huberman for careful editing and discussion of the manuscript. Owing to space constrains we were unable to cite all studies relevant to topics discussed. Aspects of this work were supported by grants from the US Public Health Service (NS45150, NS47308, NS41438, NS49088, NS10580, AG05146, AG14248, MH086881, NS047225, and TW008019), as well as the Metropolitan Life Foundation, Adler Foundation, Alzheimer’s Association, American Health Assistance Foundation, Rotary CART Fund, Wallace Foundation, Ellison Medical Foundation, and Bristol-Myers Squibb Foundation.

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

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Keywords

ASJC Scopus subject areas

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