title: A multistep validation process of biomarkers for preclinical drug development.
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.
authors.affiliation: Functional Genomics Core Facility, Penn State College of Medicine, Hershey, PA 17033, USA. wfreeman@psu.edu
authors.forename: W M
authors.initials: WM
authors.lastname: Freeman
authors.forename: G V
authors.initials: GV
authors.lastname: Bixler
authors.forename: R M
authors.initials: RM
authors.lastname: Brucklacher
authors.forename: C-M
authors.initials: CM
authors.lastname: Lin
authors.forename: K M
authors.initials: KM
authors.lastname: Patel
authors.forename: H D
authors.initials: HD
authors.lastname: VanGuilder
authors.forename: K F
authors.initials: KF
authors.lastname: LaNoue
authors.forename: S R
authors.initials: SR
authors.lastname: Kimball
authors.forename: A J
authors.initials: AJ
authors.lastname: Barber
authors.forename: D A
authors.initials: DA
authors.lastname: Antonetti
authors.forename: T W
authors.initials: TW
authors.lastname: Gardner
authors.forename: S K
authors.initials: SK
authors.lastname: Bronson
mesh_terms: D000818:Animals; D054316:Biomarkers, Pharmacological / Q000032:analysis*; D030541:Databases, Genetic; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000235:genetics; D003930:Diabetic Retinopathy / Q000188:drug therapy / Q000235:genetics; D055808:Drug Discovery / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D023381:Endpoint Determination; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D005819:Genetic Markers / Q000235:genetics; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D007328:Insulin / Q000008:administration & dosage / Q000627:therapeutic use; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results
chemical_list: D054316:Biomarkers, Pharmacological; D005819:Genetic Markers; D007004:Hypoglycemic Agents; D007328:Insulin