Lysosomal storage diseases (LSDs) result from genetic mutations in one of 42 different lysosomal proteins, 12 of which are involved in the enzymatic catabolism or degradation of sphingolipids and glycosphingolipids (GSLs). Although fully two-thirds of all LSDs have some CNS involvement that can result in progressive cognitive and motor decline, there are currently no effective therapies. There are, however, two effective approaches to treating LSDs in the periphery. The first is enzyme replacement therapy (ERT), in which the defective enzyme is supplemented with recombinant protein that has been terminally modified to be taken up into the lysosome. The second approach entails inhibition of GSL synthesis with small molecules (substrate reduction therapy or SRT), and this strategy has been clinically proven to be effective for the treatment of Gaucher type 1 disease. To date SRT has focused on inhibition of glucosylceramide (GlcCer) synthase, which catalyzes the first step in GSL synthesis. The only approved agent, miglustat, is a weak inhibitor which has limited efficacy only against Gaucher type 1 and possesses some off-target effects. A much more potent and selective inhibitor, eliglustat tartrate, is currently in phase 3 clinical trials for Gacher type 1 with reported efficacy superior to that of the ERT agent, imiglucerase. Unfortunately, eliglustat tartrate does not penetrate the CNS, so holds no promise for treating CNS-based LSDs. We recently demonstrated that a structural analog of eliglustat (CCG-203586), designed to be more CNS-permeable, was able to effect measurable reductions in GlcCer levels in the brains of mice. However, based on its close structural relationship to eliglustat, which is known to be rapidly metabolized in mice, it is unlikely that CCG-203586 will be an optimal probe for studying chronic inhibition of GSL synthesis in murine models of CNS-based LSDs. The overarching goal of this work will be to determine if SRT is an effective approach to ameliorating the symptoms of LSDs of the CNS. Our approach will be to: 1) optimize the CCG-203586 lead structure for metabolic stability and CNS-permeability without sacrificing potency, 2) evaluate the best new analogs for their degree of penetrance into the CNS of mice, and 3) select optimal probes for long-term studies in mouse models of the CNS-based LSDs: Sandhoff and Tay-Sachs. Our proposal is innovative in its use of physical property-based design to reduce recognition by efflux transporters (e.g. MDR1) at the blood brain barrier, and by the use of dual cell-based assays for GlcCer synthase inhibition that simultaneously measure both activity and recognition by MDR1. This work will be significant in allowing, for the first time, investigation o the effects of chronic inhibition of GlcCer synthase in the CNS on GSL dynamics and on development and progression of symptoms in animal models of CNS-based LSDs. Finally, the ultimate impact of our work will be progress toward the first therapy for an unmet medical need, viz. CNS-based glycosphingolipidoses.

Public Health Relevance

The mission of the NINDS is to reduce the burden of neurological disease. Currently, patients suffering from the devastating effects of neuronopathic lysosomal storage diseases (e.g. Sandhoff and Tay Sachs) have no effective treatment options. We propose to develop CNS-permeable in vivo probes to study whether synthesis inhibition therapy, which has been shown to be effective at treating lysosomal storage disease outside of the CNS, is a viable option for treating CNS-based diseases. A successful outcome of our aims would significantly advance a new therapeutic approach for an unmet medical need in the area of neurological disease.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-MDCN-C (58))
Program Officer
Tsilou, Katerina
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Michigan Ann Arbor
Schools of Pharmacy
Ann Arbor
United States
Zip Code
Shayman, James A (2018) Targeting Glucosylceramide Synthesis in the Treatment of Rare and Common Renal Disease. Semin Nephrol 38:183-192
Dupre, Tess V; Doll, Mark A; Shah, Parag P et al. (2017) Inhibiting glucosylceramide synthase exacerbates cisplatin-induced acute kidney injury. J Lipid Res 58:1439-1452
Shayman, James A (2016) Targeting Glycosphingolipid Metabolism to Treat Kidney Disease. Nephron 134:37-42
Shayman, James A (2015) Challenges and opportunities in the development of therapeutics for chronic kidney disease. Transl Res 165:482-7
Glukhova, Alisa; Hinkovska-Galcheva, Vania; Kelly, Robert et al. (2015) Structure and function of lysosomal phospholipase A2 and lecithin:cholesterol acyltransferase. Nat Commun 6:6250
Shayman, James A; Larsen, Scott D (2014) The development and use of small molecule inhibitors of glycosphingolipid metabolism for lysosomal storage diseases. J Lipid Res 55:1215-25