Development of a Small Molecule Therapy for Metachromatic Leukodystrophy

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DESCRIPTION (provided by applicant): The objective of this Phase I SBIR proposal is to develop a central nervous system penetrant (CNS) small molecule therapy for Metachromatic Leukodystrophy (MLD). We will accomplish this by developing a cellular model of MLD to screen compound libraries in order to identify small molecule screening hits suitable for lead optimization to develop drugs for the treatment of this devastating disease. MLD is a rare genetic condition found in 1 in 40,000 births that is caused by a deficiency in the lysosomal arylsulfatase A (ASA) or saposin B (SAPB) [1, 2]. The lack of ASA activity leads to widespread accumulation of 3-O sulfated glycolipids in the lysosomes of cells. The accumulation of sulfated glycolipids in oligodendrocytes and neurons in the CNS leads to the profound neurological deterioration and ultimately death. In this proposal, we aim to change this situation by developing a model of MLD based on cells from patients with MLD. This assay will enable the high throughput screening of compound libraries in order to identify novel treatments for this destructive disease. To accomplish this, we propose to develop rapid analytical method for the quantitation of the primary 3-O sulfated glycolipid (sulfatide) that accumulates in cultured human MLD cells. This assay will be used to screen compound libraries for inhibitors of lysosomal sulfatide storage. Finally, the hits will be prioritized based on their mechanisms, potency, ADME, and PK properties. Upon successful completion of this proposal, we will have identified the hit compounds that can serve as the starting point for the discovery and development of a novel CNS penetrant therapy for MLD. PUBLIC HEALTH RELEVANCE: This research is designed to identify a treatment for Metachromatic Leukodystrophy, a genetic condition that causes severe neurological disease. There are currently no effective therapeutic options for this life threatening disease. If successful, this research could lead to a therapy for Metachromatic Leukodystrophy.