Pharmacological Chaperone Therapy for the GM2 Gangliosidoses

Project Summary Abstract Pharmacological Chaperone Therapy for the GM Gangliosidoses The ultimate goal of this application is the treatment of Tay Sachs DiseaseTSDand Sandhoff DiseaseSDcollectively called the GMGangliosidoses with a small molecule pharmacological chaperonePharmacological chaperonesPCsare small molecules that selectively bind and stabilize target proteins to facilitate proper foldingreduce premature degradation and increase the efficiency of ER exportThis approach is broadly applicable to diseases where increasing the function of a specific proteinmutant or wild typeis predicted to provide therapeutic benefitOTis a potenthexosaminidasethe deficient enzyme in these diseasestargeted pharmacological chaperone with good bioavailabilityblood brain barrier penetrationhigh selectivity forhexosaminidase and low cytotoxicityOTtreatment increases levels of wildtype and mutanthexosaminidase activity up tofold in cellsOrPhi Therapeutics has developed the only mouse modelRQRQin which a pharmacological chaperone therapy can be tested for dosing and efficacyWe intend to use this model to test our pharmacological chaperone OTin long term dosing and efficacy studiesAdditionallywe intend to develop a cell based assay that discriminates between OTresponsive and nonresponsive variants of Hex A and Hex B to determine which Tay Sachs and Sandhoff Disease patients will be amenable to pharmacological chaperone therapy with OTin future clinical trialsThe GMGangliosidoses are life threatening neurodegenerative diseases for which no treatment is currently availableThe focus of this work is to provide pre clinical data to support the development of OTthrough IND enabling studies and subsequent clinical trials for the GMGangliosidoses