Grant: CIHR Fellowship

Lysosomal storage disorders (LSDs) are a large group of genetic diseases and the most common type of pediatric neurodegenerative disease. Gaucher disease (GD) is the most prevalent of the LSDs. It causes enlargement of the spleen and liver, painful bone lesions, anemia and, in some cases, neurological impairment. The cells of patients with GD lack enough of an enzyme called glucocerebrosidase (GCase) to function normally - this enzyme deficiency is caused by a simple mutation. When enzymes are manufactured in cells, they must fold in a certain way to function correctly. Incorrectly folded enzymes are usually disassembled by the 'quality control machinery' within a cell. The mutations that cause GD make it very difficult for newly manufactured GCase to fold correctly. As a consequence, most of the GCase that is produced by GD patients is prematurely degraded. There are three types of GD; only one can be treated effectively. Those that can be treated receive regular injections of a synthetic GCase. Unfortunately, this therapy is extremely expensive; one year of treatment costs in excess of $200k. Clearly, more general, effective, and economical therapeutics for GD are needed. Enzyme enhancement therapy is an emerging technology that uses small molecules to improve a patient's ability to make an enzyme that they are deficient in. The idea is that if small molecules can be found that help an enzyme fold correctly during its production, more of that enzyme will avoid degradation and proceed to perform its designated task within the cell. Such molecules are referred to as pharmacological chaperones (PCs). The goal of the proposed research is to identify a range of new PCs for GCase. A large collection of molecules based on compounds known to stabilize GCase will be prepared and their ability to improve GCase production in cells from GD patients will be assessed. Promising candidates will be studied in more complex systems, with the view to develop a new therapy for GD.