Abstract
Glycosphingolipid (GSL) storage diseases have been the focus of efforts to develop small molecule therapeutics from design, experimental proof of concept studies, and clinical trials. Two primary alternative strategies that have been pursued include pharmacological chaperones and GSL synthase inhibitors. There are theoretical advantages and disadvantages to each of these approaches. Pharmacological chaperones are specific for an individual glycoside hydrolase and for the specific mutation present, but no candidate chaperone has been demonstrated to be effective for all mutations leading to a given disorder. Synthase inhibitors target single enzymes such as glucosylceramide synthase and inhibit the formation of multiple GSLs. A glycolipid synthase inhibitor could potentially be used to treat multiple diseases, but at the risk of lowering nontargeted cellular GSLs that are important for normal health. The basis for these strategies and specific examples of compounds that have led to clinical trials is the focus of this review.
Highlights
Glycosphingolipid (GSL) storage diseases have been the focus of efforts to develop small molecule therapeutics from design, experimental proof of concept studies, and clinical trials
There are more than 50 lysosomal storage diseases (LSDs) that can arise in this way [2]
“glycosphingolipidoses” that have been recognized as LSDs are Gaucher disease types 1, 2, and 3, Fabry disease, Tay-Sachs and Sandhoff disease, and GM1 gangliosidosis
Summary
Hepatomegaly, anemia, thrombocytopenia, bone disease (type 1); seizures, cognitive impairment (types 2 and 3). These include a very high cost [10], the requirement for intravenous administration, the failure of the infused protein to distribute adequately to target tissues, the development of antibodies to the enzyme resulting in loss of therapeutic efficacy, and the inability of the lysosomal protein to cross the blood-brain barrier. Other strategies for “enzyme replacement” in addition to the use of recombinant mannose-terminated enzyme have been explored These include bone marrow transplantation [12], gene therapy [13, 14], and more recently stem cell therapy [15]. This review will highlight selected examples in the discovery and development of compounds that have been the subject of clinical trials
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