Orphanet-Canada
Research Project
Title
Enzyme Enhancement Therapy for GM1 Gangliosidosis
Project Description
GM1 gangliosidosis (GM1) is 1 of ~50 Lysosomal Storage Diseases (LSDs). Although each LSD is rare as a group they account for ~1/5000 births, making them an important health problem in Canada. LSDs are genetic disorders caused by a deficiency of a single lysosomal enzyme, which for GM1 is beta-galactosidase (b-Gal). The storage material, GM1 ganglioside, is primarily made in the brain, leading to progressive neurodegeneration. No therapy is currently available for GM1. Enzyme replacement therapy has proven effective for ~5 LSDs, but cannot treat LSDs that affect the brain. For these LSDs, like GM1, small molecule based therapies hold the most promise, as they can often reach, and thus treat, the brain. One such approach is Enzyme Enhancement Therapy (EET), which uses small drug-like molecules called pharmacological chaperones (PCs). PCs are able to stabilize a mutant protein preventing its misfolding, allowing it to reach the lysosome and degrade the storage material. However, PCs are not effective for every type of mutation. We have successfully developed EETs for 2 other LSDs (Gaucher and adult Tay-Sachs) and will build on these successes to identify PCs for GM1. Two complementary small molecule libraries will be screened. A direct assay using live cells from a GM1 patient (determined by us to be responsive to EET) has been developed and is currently being used to screen the largest of these two libraries (30,000 compounds). Here we propose to complete this primary screening and further characterize and validate 10 - 20 of the compounds that produced the best enhancement of b-Gal activity in GM1 cells. The structure of the resulting lead compound(s) will then be chemically optimized for maximum efficacy. Ultimately, the optimized PC will be tested in a unique feline model of naturally occurring GM1, whose cells we have confirmed to respond to EET, by measuring levels of b-gal activity and GM1 ganglioside storage in the brain of treated versus untreated felines.
Principal Investigator
Don Mahuran, The Hospital for Sick Children Research Institute