Steven Wagner earned his MS and PhD degrees in biochemistry from the University of Louisville School of Medicine and did post-doctoral training in microbiology and molecular genetics and UC Irvine College of Medicine.
He then served as Director of Biochemistry at the Salk institute Biotechnology/Industrial Associates, Inc., followed by a position as Chief Scientific Officer at Neurogenetics, Inc./TorreyPines Therapeutics, Inc. In 2009 he joined UC San Diego's Department of Neurosciences, where he currently is an associate professor and principal investigator.
Dr. Wagner's research focuses on the discovery, design and preclinical development of therapeutic small molecules known as gamma-secretase modulators (GSaMs). These drug-like small molecules are aimed at preventing and/or delaying the buildup of specific neuropathological lesions known as neuritic plaques that are invariably abundant in the brains of both patients with Down syndrome and Alzheimer's disease.
Dr. Wagner led the team that discovered the first non-NSAID-like and truly “Notch-sparing” gamma-secretase modulators and introduced the term “gamma-secretase modulators or GSMs” in 2005 (through the discovery of a novel series of diaryl-2-aminothiazole derivatives that are over 5000-fold more potent at lowering Aβ42 levels as are the NSAID-like “substrate-targeted” gamma-secretase modulators, e.g., sulindac sulphide and tarenflurbil).
Since moving into the Department of Neurosciences at UCSD in 2009, his laboratory, in addition to designing/discovering another novel and structurally distinct, yet mechanistically-related 2-aminothiazole-containing GSM chemotype, has procured and validated all of the necessary immunochemical tools and differential screening assays (including high-throughput screening or HTS assays).
In 2011 Dr. Wagner's team was awarded one of only seven Blueprint Neurotherapeutics (BPN) U01s by NIH/NINDS to optimize and develop more water soluble GSMs for Alzheimer’s disease (AD). These novel GSMs, termed soluble gamma-secretase modulators or SGSMs, have significantly improved physicochemical properties compared to the original GSM series.
During the first three years of the project, his team has synthesized and identified a large number (>350) GSMs and also identified a subset of these which have excellent potency, brain penetration and oral bioavailability. They expect to begin IND enabling studies with their clinical candidate in 2014.
Recent Peer-Reviewed Publications
Varvel NH, Bhaskar K, Kounnas MZ, Wagner SL, Yang Y, Lamb BT and Herrup K NSAIDs prevent but not reverse, neuronal cell cycle reentry in a mouse model of Alzheimer’s disease 2009 J Clin Invest 119: 3692-3702 (PMID 19907078)
Salehi A, Faizi M, Coals D, Valetta J, Laguna J, Takimoto-Kimura R, Kleschevnikov A, Wagner SL, Aisen P, Shamloo M and Mobley WC Restoration of norepinephrine-modulated contextual memory in a mouse model of Down Syndrome 2009 Sci Transl Med 1: p7ra17 (DOI: 10.1126scitranslmed.3000258) (PMID 20368182)
Kounnas MZ, Danks AM, Cheng S, Tyree C, Mao L, Comer D, Yu C, Pleynet D, Nyugen P, Digregorio PJ, Page N, Ackerman E, Velicelebi G, Stauderman KA, Sisodia SS, Comer WT, Tanzi RE and Wagner SL Modulation of gamma secretase in vivo reduces beta-amyloid deposition in a transgenic mouse model of Alzheimer’s disease 2010 Neuron 67: 769-780 (PMID 20826309)
Vetrivel KS, Barman A, Chen Y, Nguyen PD, Wagner SL, Prabhakar R and Thinakaran G Loss of cleavage at β’-site contributes to apparent increase in β-amyloid peptide (Abeta) secretion by Beta-secretase (BACE1)-glycosylphosphatidylinositol (GPI) processing of amyloid precursor protein 2011 J. Biol. Chem. 286: 26166-26177 (PMID 21642424)
Wagner SL, Tanzi RE, Mobley WC and Galasko D Potential of gamma-secretase modulators in the treatment of Alzheimer’s disease 2012 Arch Neurol 69:1255-1258 (PMID 22801784)
Wagner SL, Zhang C, Cheng S, Nguyen P, Zhang X, Rynearson KD, Wang R, Sisodia SS, Mobley WC and Tanzi RE Soluble y-Secretase Modulators Selectively Inhibit Production of the 42-Amino Acid Amyloid β Peptide Variant and Augment the Production of Multiple Carboxy-Truncated Amyloid β Species 2014 Biochemistry doi.org/10.1021/bi401537v (PMID 24401146)