Gary Lee
Amicus Therapeutics
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Publication
Featured researches published by Gary Lee.
Journal of Medicinal Chemistry | 2013
Robert E. Boyd; Gary Lee; Philip J. Rybczynski; Elfrida R. Benjamin; Richie Khanna; Brandon Wustman; Kenneth J. Valenzano
Lysosomal enzymes are responsible for the degradation of a wide variety of glycolipids, oligosaccharides, proteins, and glycoproteins. Inherited mutations in the genes that encode these proteins can lead to reduced stability of newly synthesized lysosomal enzymes. While often catalytically competent, the mutated enzymes are unable to efficiently pass the quality control mechanisms of the endoplasmic reticulum, resulting in reduced lysosomal trafficking, substrate accumulation, and cellular dysfunction. Pharmacological chaperones (PCs) are small molecules that bind and stabilize mutant lysosomal enzymes, thereby allowing proper cellular translocation. Such compounds have been shown to increase enzyme activity and reduce substrate burden in a number of preclinical models and clinical studies. In this Perspective, we review several of the lysosomal diseases for which PCs have been studied and the SAR of the various classes of molecules.
Assay and Drug Development Technologies | 2011
Kenneth J. Valenzano; Richie Khanna; Allan C. Powe; Robert Boyd; Gary Lee; John J. Flanagan; Elfrida R. Benjamin
Many human diseases result from mutations in specific genes. Once translated, the resulting aberrant proteins may be functionally competent and produced at near-normal levels. However, because of the mutations, the proteins are recognized by the quality control system of the endoplasmic reticulum and are not processed or trafficked correctly, ultimately leading to cellular dysfunction and disease. Pharmacological chaperones (PCs) are small molecules designed to mitigate this problem by selectively binding and stabilizing their target protein, thus reducing premature degradation, facilitating intracellular trafficking, and increasing cellular activity. Partial or complete restoration of normal function by PCs has been shown for numerous types of mutant proteins, including secreted proteins, transcription factors, ion channels, G protein-coupled receptors, and, importantly, lysosomal enzymes. Collectively, lysosomal storage disorders (LSDs) result from genetic mutations in the genes that encode specific lysosomal enzymes, leading to a deficiency in essential enzymatic activity and cellular accumulation of the respective substrate. To date, over 50 different LSDs have been identified, several of which are treated clinically with enzyme replacement therapy or substrate reduction therapy, although insufficiently in some cases. Importantly, a wide range of in vitro assays are now available to measure mutant lysosomal enzyme interaction with and stabilization by PCs, as well as subsequent increases in cellular enzyme levels and function. The application of these assays to the identification and characterization of candidate PCs for mutant lysosomal enzymes will be discussed in this review. In addition, considerations for the successful in vivo use and development of PCs to treat LSDs will be discussed.
Journal of Pharmacology and Experimental Therapeutics | 2010
Patricia René; Christian Le Gouill; Irina D. Pogozheva; Gary Lee; Henry I. Mosberg; I. Sadaf Farooqi; Kenneth J. Valenzano; Michel Bouvier
Heterozygous null mutations in the melanocortin-4 receptor (MC4R) cause early-onset obesity in humans, indicating that metabolic homeostasis is sensitive to quantitative variation in MC4R function. Most of the obesity-causing MC4R mutations functionally characterized so far lead to intracellular retention of receptors by the cells quality control system. Thus, recovering cell surface expression of mutant MC4Rs could have a beneficial therapeutic value. We tested a pharmacological chaperone approach to restore cell surface expression and function of 10 different mutant forms of human melanocortin-4 receptor found in obese patients. Five cell-permeant MC4R-selective ligands were tested and displayed pharmacological chaperone activities, restoring cell surface targeting and function of the receptors with distinct efficacy profiles for the different mutations. Such mutation-specific efficacies suggested a structure-activity relationship between compounds and mutant receptor conformations that may open a path toward personalized therapy. In addition, one of the five pharmacological chaperones restored function to most of the mutant receptors tested. Combined with its ability to reach the central nervous system and its selectivity for the MC4R, this pharmacological chaperone may represent a candidate for the development of a targeted therapy suitable for a large subset of patients with MC4R-deficient obesity.
Archive | 2010
Robert Boyd; Gary Lee; Philip J. Rybczynski
Archive | 2010
Robert Boyd; Gary Lee; Philip J. Rybczynski
Archive | 2010
Robert Boyd; Gary Lee
Molecular Genetics and Metabolism | 2011
Sean W. Clark; Gary Lee; Robert Boyd; Sean Sullivan; Lee Pellegrino; Michelle Frascella; Richie Khanna; Nastry Brignol; Brandon Wustman; Philip J. Rybczynski; Elfrida R. Benjamin; Kenneth J. Valenzano; David J. Lockhart
Archive | 2017
Gary Lee; Robert Boyd
Archive | 2015
Robert Boyd; Gary Lee
Alzheimers & Dementia | 2012
Anthony Stevens; Carolyn Collins; Evan Katz; Gary Lee; Vernon Alford; Hadis Williams; Darlene Guillen; Xiaoyang Wu; John J. Flanagan; Eric Sjoberg; Sam Gandy; David J. Lockhart; Brandon Wustman; Leo Dungan