Small molecules to reduce the levels of polyglucosan bodies in fibroblasts derived from Adult Polyglucosan Body Disease patients
Adult Polyglucosan Body Disease (APBD) and infant Glycogen Storage Disease type IV are rare neurodegenerative disorders caused by mutations in the gene encoding glycogen-branching enzyme and ensuing deficiency of the GBE protein. The current proof of concept is relevant for treating not only other types of Glycogen storage diseases but also diseases caused by destabilizing mutations in protein surface-exposed regions. APBD and other PB-based diseases as well as glycogen storage diseases in general are Orphan Diseases, some being ultra-rare, and most lack any available treatment. Beyond the value of OD designation affording significant advantages, many orphan drugs have significant markets in the range of $100Ms, even >$1B.
A cell-based assay was developed to identify small molecule (SMC) inhibitors of PB formation from an APBD patient. Eleven SMC hits show favorable dose-response profiles and are non-toxic in animals and improve the symptoms in animal, and hence canbe usefulas a drug to treat PB-based diseases.
•In vitro proof of concept
•In vivosafety tests.
•Ongoing efficacytests in genetic models.
NovelCompounds that can be used for a cost-effective treatment of glycogen storage disorders using an ultra-rare disease for entry, in a market dominated by expensive Enzyme Replacement Therapies.
Dr. Or Kakhlon
Dr. Miguel Weil