ExSAR’s Interest Deﬁned
Compounds that stabilize an overly dynamic structure and restore proper folding and trafficking are known as pharmacological chaperones (PCs). ExSAR’s screening and hydrogen deuterium exchange technologies are uniquely suited to PC identification and characterization.
Because protein synthesis of lysosomal protein is well understood, and the market potential of a single class of therapeutics, e.g., enzyme replacement therapy, is a multi-billion dollar opportunity, development of PCs for Gaucher and Tay-Sachs diseases are attractive targets for drug development.
From among approximately 50 Lysosomal Storage Disorders (LSDs) identified to date, two were chosen as initial indications for ExSAR’s PC strategy – Late Onset Tay-Sachs (LOTS) and Gaucher disease. Both Tay-Sachs and Gaucher diseases are inherited conditions resulting in the abnormal accumulation of glycolipids; Tay-Sachs, due to a deficiency in the enzymatic activity of Hexosaminidase-A (HexA) and Gaucher, due to a deficiency in the enzymatic activity of beta-glucocerebrosidase (GCase).
ExSAR’s strategy is to seek small molecules that restore native conformation and behavior, thus restoring lysosomal concentrations of the mutant enzyme.
A strategic focus on protein misfolding diseases and lysosomal storage disorders
Protein misfolding diseases encompass a broad group of disorders whereby the folding of a protein under environmental or mutational stress is impaired resulting in genetic and epigenetic pathological phenotypes. Increasingly, the scientific and medical communities accept that common metabolic misfolding of proteins causes inflammatory, neurological, psychiatric and other disorders, and the molecular cascades deployed under conditions of allostasis (the process by which the body responds to stressors in order to regain homeostasis).
Genetic disease is a common cause of conformational change. Mendelian mutation, particularly missense mutation, leads to an abnormal protein with abrogated function. In the extreme, the mutated protein may not function at all. Diseases with complex genetics (e.g., adult onset diabetes mellitus, Alzheimer’s disease, Parkinson disease, ALS, etc.) also cause conformational changes as assessed by the deposition of complex proteic material (e.g., Lewy bodies, tangles, etc.).
Approximately 50 diseases have been attributed to dysfunctional protein function within the lysosome and, likely, many others will be identified in the future. Macromolecules are degraded in a regulated and stepwise process in the lysosome. When this process fails, an abnormal accumulation of undigested or partially digested intermediates leads to lysosomal storage disorders (LSDs).
Lysosomal storage disorders, a sub-segment within the protein misfolding disease group, result when a specific organelle in the body’s cells – the lysosome – malfunctions.
Lysosomal storage disorders are caused by lysosomal dysfunction usually as a consequence of deficiency of a single enzyme required for the metabolism of lipids, glycoproteins (sugar containing proteins) or so-called mucopolysaccharides. Individually, LSDs occur with incidences of less than 1:100,000; however, as a group the incidence is about 1:5,000 – 1:10,000.
The lysosome is commonly referred to as the cell’s recycling center because it processes unwanted material into substances that the cell can utilize. Lysosomes break down this unwanted matter via enzymes, highly specialized proteins essential for survival.
Lysosomal disorders are triggered when a particular enzyme exists in too small an amount or is missing altogether. When this happens, substances accumulate in the cell. In other words, when the lysosome doesn’t function normally, excess products destined for breakdown and recycling are stored in the cell.
Like other genetic diseases, individuals inherit lysosomal storage diseases from their parents. Although each disorder results from different gene mutations that translate into a deficiency in enzyme activity, they all share a common biochemical characteristic – all lysosomal disorders originate from an abnormal accumulation of substances inside the lysosome.
Lysosomal storage diseases affect mostly children and they often die at a young and unpredictable age, many within a few months or years of birth. Many other children die following years of suffering from various symptoms of their particular disorder.
Diseases linked to lysosomal storage disorders: