Greater than 75 lysosomal proteins have been characterized, and genetic mutations in 42 of these proteins result in clinically unique lysosomal storage diseases. Of these disorders, 14 are the result of impaired catabolism of sphingolipids and 8 are due to the impaired degradation of glycosphingolipids. The traditional approach for treating these disorders has been through the use of mannose or mannose-6-phosphate terminated recombinant proteins as the basis for enzyme replacement therapy. An alternative approach, now clinically proven for the treatment of type 1 Gaucher disease, is the use of synthesis inhibition therapy. By targeting the first synthetic step in glycosphingolipid synthesis, glucosylceramide synthase, potent small molecule inhibitors were designed as highly active lead compounds for the treatment of Gaucher type 1 and Fabry disease. One compound in this series, eliglustat tartrate, has been demonstrated to be as efficacious as imiglucerase in phase 2 trials and is currently the basis for two phase 3 studies for type 1 Gaucher disease. Because eliglustat tartrate does not cross the blood brain barrier, it is unsuitable for the treatment of several glycosphingolipidoses with CNS involvement that include types 2 and 3 Gaucher disease, early and late onset Tay-Sachs disease, and GM1 gangliosidosis. With funding from a prior R21 award, the applicants undertook the property-based design of inhibitors of glucosylceramide synthase that lack recognition by the multidrug resistance transporter MDR1 utilizing the previously defined pharmacophore for eliglustat tartrate. Using considerations of conformational mobility and topological polar surface area, an analog of eliglustat was identified that retained activity against glucosylceramide synthase in the low nanomolar range, lacked recognition by MDR1 in two in vitro assays, and was shown to lower brain glucosylceramide levels in wild type mice with short term dosing. We now propose to study this compound, 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-(2,3- dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide (CCG-203586), in a suitable mouse model of type 3 Gaucher disease to ascertain whether it is an appropriate candidate for clinical development. The following hypothesis is to be tested. CCG-203586 will delay or prevent the onset of neurological deterioration and death in models of the neuronopathic Gaucher mouse.
The specific aims of this project include the following: 1. To ascertain the optimal formulation of CCG-203586 for oral dosing. 2. To establish an assay for the measurement of CCG-203586 in blood and tissues, including brain. 3. To perform pharmacokinetic studies in wild type mice to determine the bioavailability, half-life, distribution, metabolism, and excretion of CCG-203586. 4. To treat the neuronopathic Gaucher mice with CCG-203586 either orally or parenterally to determine its efficacy in lowering peripheral tissue and brain glucosylceramide accumulation, delaying or preventing death, preventing histopathological changes in the brain, and inflammatory changes in the brain and peripheral tissues.

Public Health Relevance

Lysosomal storage disorders are rare inherited diseases resulting in the abnormal accumulation of cellular compounds. The principal investigator has successfully developed an oral therapy, eliglustat tartrate, for one such disease termed type 1 Gaucher disease. In concept, this therapy might work for related diseases but is limited by the inability of the drug to distribute into the brain. Working with a group in the College of Pharmacy the principal investigator has developed a related drug candidate that distributes into the brain and retains its activity against the targeted pathway. In this grant they propose to study the new compound in a mouse model of Gaucher disease that affects the brain. Preliminary work on the activity and dosing of the drug will precede a proof of principle study in the mouse model. The proposed studies represent necessary next steps in the possible development of this compound for human trials.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Morris, Jill A
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University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
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