Pharmacological Chaperone Therapy for the GM2Gangliosidoses. The ultimate goal of this application is the treatment of Tay-Sachs Disease (TSD) and Sandhoff Disease (SD) collectively called the GM2 Gangliosidoses with the small molecule pharmacological chaperone, OT1001. Pharmacological chaperones (PCs) are small molecules that selectively bind and stabilize target proteins to facilitate proper folding, reduce premature degradation and increase the efficiency of ER export. This approach is broadly applicable to diseases where increasing the function of a specific protein (mutant or wild-type) is predicted to provide therapeutic benefit. OT1001 is a potent -hexosaminidase (the deficient enzyme in these diseases) targeted pharmacological chaperone with good bioavailability, blood-brain barrier penetration, high selectivity for -hexosaminidase and low cytotoxicity. OT1001 treatment increases levels of wild-type and mutant -hexosaminidase activity up to 3-fold in cells and in wild-type mouse brain tissue when orally administered Specifically OrPhi Therapeutics will determine the potency of OT1001 for the R505Q mutant form of -hexosaminidase in a SD patient fibroblast cell line. This will allow us to determine the dose range of OT1001 that will need to be achieved when using a novel animal model in which the Hex B SD mutation R505Q is expressed on a -Hex -/- background for pre-clinical dosing studies. This newly created mouse model is the only mouse model in which a pharmacological chaperone can be tested for dosing and possibly efficacy. Additionally, we intend to develop a cell based assay that discriminates between OT1001 responsive and non-responsive variants of Hex A and Hex B to determine which Tay-Sachs and Sandhoff Disease patients will be amenable to pharmacological chaperone therapy with OT1001 in future clinical trials. The GM2 Gangliosidoses are life threatening neurodegenerative diseases for which no treatment is currently available. The focus of this work is to provide pre-clinical data to support the development of OT1001 through IND enabling studies and subsequent clinical trials for the GM2 Gangliosidoses.

Public Health Relevance

Tay-Sachs disease and Sandhoff Disease or the GM2 Gangliosidoses are related genetic disorders that result from a deficiency of the enzyme beta-hexosaminidase. This enzyme catalyzes the degradation of glycoconjugates including gangliosides. These diseases are rare diseases with severe central nervous system manifestations and currently there is no effective therapy. This research could ultimately lead to an effective therapy for the GM2 Gangliosidoses.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
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Special Emphasis Panel (ZRG1)
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Morris, Jill A
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Orphi Therapeutics, Inc.
United States
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