Lysosomes are subcellular organelles containing catabolic enzymes which breakdown macromolecules for recycling. One class of macromolecules, glycosphingolipid, is an essential cell membrane component containing polysaccharide chains of various lengths. Lysosomes contain at least 50-60 enzymes that target and sequentially degrade these polysaccharide chains (substrates). Mutations in genes encoding these enzymes can result in defects that impede catabolism and lead to the pathological buildup of substrate . Diseases arising from the pathological buildup of substrate are known as lysosomal storage disorders . More than 50 lysosomal storage disorders have been identified to date, most of these due to a deficiency of a single lysosomal enzyme. Some of these mutations result in disease because they adversely affect the folding rate and/or slightly destabilize the lysosomal enzyme. Proteins destined for secretion or trafficking to the lysosome are first co-translated into the lumen of the endoplasmic reticulum (ER). There they either quickly fold into their proper (native) three dimensional structure, or following repeated folding failures, undergo detection by the ER quality control machinery, whereupon they are subsequently degraded. Mounting evidence suggests that slight to moderately destabilizing mutations which do not obliterate enzymatic activity never-the-less trigger quality control detection and destruction. Therapies that stabilize the mutant enzyme and allow for lysosomal trafficking could impart a positive therapeutic benefit. ExSAR’s strategy is to seek small molecules that restore native conformation and behavior, thus restoring lysosomal concentrations of the mutant enzyme.

Lysosomal Storage Disorders and Protein Misfolding | Product Pipeline | Clinical Trials