title: New applications of disease genetics and pharmacogenetics to drug development.
abstract: TOMMORROW is a Phase III delay of onset clinical trial to determine whether low doses of pioglitazone, a molecule that induces mitochondrial doubling, delays the onset of MCI-AD in normal subjects treated with low dose compared to placebo. BOLD imaging studies in rodents and man were used to find the dose that increases oxygen consumption at central regions of the brain in higher proportion than activation of large corticol regions. The trial is made practical by the use of a pharmacogenetic algorithm based on TOMM40 and APOE genotypes and age to identify normal subjects at high risk of MCI-AD between the ages of 65-83 years within a five year follow-up period.
authors.affiliation: Zinfandel Pharmaceuticals, Inc., Durham, NC, United States; Duke University Medical Center, Department of Neurology, Durham, NC, United States. Electronic address: roses@zinfandelpharma.com.
authors.forename: Allen D
authors.initials: AD
authors.lastname: Roses
authors.affiliation: Duke University Medical Center, Department of Neurology, Durham, NC, United States.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Saunders
authors.affiliation: Duke University Medical Center, Department of Neurology, Durham, NC, United States.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Lutz
authors.affiliation: Pennsylvania State University, Department of Biomedical Engineering, State College, PA, United States.
authors.forename: Nanyin
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Duke University Medical Center, Department of Neurology, Durham, NC, United States.
authors.forename: Ahmad R
authors.initials: AR
authors.lastname: Hariri
authors.affiliation: Takeda Pharmaceuticals, Deerfield, IL, United States.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Asin
authors.affiliation: Zinfandel Pharmaceuticals, Inc., Durham, NC, United States.
authors.forename: Donna G
authors.initials: DG
authors.lastname: Crenshaw
authors.affiliation: Takeda Pharmaceuticals, Deerfield, IL, United States.
authors.forename: Kumar
authors.initials: K
authors.lastname: Budur
authors.affiliation: Zinfandel Pharmaceuticals, Inc., Durham, NC, United States.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Burns
authors.affiliation: Takeda Pharmaceuticals, Deerfield, IL, United States.
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Brannan
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D000544:Alzheimer Disease / Q000235:genetics / Q000517:prevention & control*; D000818:Animals; D001921:Brain / Q000473:pathology; D017326:Clinical Trials, Phase III as Topic / Q000379:methods; D060825:Cognitive Dysfunction / Q000235:genetics / Q000517:prevention & control; D015195:Drug Design; D005838:Genotype; D006801:Humans; D010597:Pharmacogenetics; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D045162:Thiazolidinediones; D000077205:Pioglitazone