James Shayman is Professor of Internal Medicine and Pharmacology and the past Associate Vice-President for Research at the University of Michigan. He received his undergraduate degree from Cornell University and his medical degree from Washington University. He trained in internal medicine and nephrology at Barnes Hospital in St. Louis and was a post-doctoral fellow in the Department of Pharmacology at Washington University. Since 1986 he has been on the faculty at the University of Michigan as a clinician and physician scientist. For the last 20 years his laboratory has devoted their efforts the study of sphingolipids in health and disease.
My work in translational research on lysosomal storage disorders has focused on four primary questions. First, is it possible to develop drugs for lysosomal storage diseases that are superior to existing therapeutics? Second, can one develop novel drugs for currently untreatable diseases? Third, are there lysosomal storage diseases that have yet to be discovered? Four, are there acquired lysosomal storage disorders? The first two questions have been pursued through the design and development of novel small molecule inhibitors of glucosylceramide synthase. Initial work focused on the structural diversification of a ceramide analogue and proof of principle studies demonstrating that glycolipid synthesis inhibition is useful for the treatment of Gaucher and Fabry disease. A lead compound resulting from this work, eliglustat tartrate, is of sufficiently high activity and specificity to serve as the basis for several late stage phase 3 clinical trials for the treatment of type 1 Gaucher disease. More recent work has focused on the property-based design of glycolipid synthesis inhibitors that cross the blood brain barrier. Such compounds may provide the basis for the treatment of CNS based glycosphingolipidoses such as Tay-Sachs and type 3 Gaucher disease, disorders for which there are no current effective therapies. In pursuit of the third and fourth questions, we have discovered and characterized a novel lysosomal enzyme, group XV phospholipase A2. This enzyme catalyzes the formation of 1-O-acylceramide via a transacylation pathway and represents the first and only acidic phospholipase A2 characterized to date. We hypothesize that group XV phospholipase A2 plays a key role in the pathogenesis of autoimmunity and is the primary target for drug induced phospholipidosis by cationic amphiphilic drugs.