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A multistep validation process of biomarkers for preclinical drug development

The Pharmacogenomics Journal volume 10, pages 385–395 (2010)Cite this article

Abstract

Biomarkers that can be measured in preclinical models in a high-throughput, reproducible manner offer the potential to increase the speed and efficacy of drug development. Development of therapeutic agents for many conditions is hampered by the limited number of validated preclinical biomarkers available to gauge pharmacoefficacy and disease progression, but the validation process for preclinical biomarkers has received limited attention. This report defines a five-step preclinical biomarker validation process and applies the process to a case study of diabetic retinopathy. By showing that a gene expression panel is highly reproducible, coincides with disease manifestation, accurately classifies individual animals and identifies animals treated with a known therapeutic agent, a biomarker panel can be considered validated. This particular biomarker panel consisting of 14 genes (C1inh, C1s, Carhsp1, Chi3l1, Gat3, Gbp2, Hspb1, Icam1, Jak3, Kcne2, Lama5, Lgals3, Nppa, Timp1) can be used in diabetic retinopathy pharmacotherapeutic research, and the biomarker development process outlined here is applicable to drug development efforts for other diseases.

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Abbreviations

DR:

diabetic retinopathy

STZ:

streptozotocin. (A full listing of gene names is given in Supplementary Table S1)

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Acknowledgements

We thank Lamont Harris for assistance with figure preparation; Wendy Dunton, Allison Collins and Sara Mendoza De Granja in the Penn State JDRF Diabetic Retinopathy Center Animal Models Core; Alan Kunselman for data analysis, Elliot Vessel, Joseph Freeman and Alanna Roff for editorial suggestions; and Janelle Roman for administrative support. This study was supported with research funding from the Juvenile Diabetes Research Foundation to WMF, SRK, AJB, DAA, KFL, SKB and TWG, as well as Pennsylvania Tobacco Settlement Funds to KFL, SRK, WMF and TWG. TWG is the Jack and Nancy Turner Professor of Ophthalmology.

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Authors and Affiliations

  1. Functional Genomics Core Facility, Penn State College of Medicine, Hershey, PA, USA

    W M Freeman, G V Bixler, R M Brucklacher & K M Patel

  2. Department of Pharmacology, Penn State College of Medicine, Hershey, PA, USA

    W M Freeman

  3. Department of Cellular & Molecular Physiology, Penn State College of Medicine, Hershey, PA, USA

    C-M Lin, K F LaNoue, S R Kimball, D A Antonetti & T W Gardner

  4. Department of Ophthalmology, Penn State College of Medicine, Hershey, PA, USA

    H D VanGuilder, A J Barber, T W Gardner & S K Bronson

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  1. W M Freeman
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  2. G V Bixler
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Correspondence to W M Freeman.

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Supplementary Information accompanies the paper on The Pharmacogenomics Journal website

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Freeman, W., Bixler, G., Brucklacher, R. et al. A multistep validation process of biomarkers for preclinical drug development. Pharmacogenomics J 10, 385–395 (2010). https://doi.org/10.1038/tpj.2009.60

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