Substrate reduction therapy

© 2007 by Taylor & Francis Group, LLC. The use of substrate reduction therapy for glycosphingolipid storage diseases was first proposed by Dr. Norman Radin. 1 It is noteworthy that Gaucher disease was the “test case” adopted for the experimental development of this postulate. Radin reasoned that, in the classical glycosphingolipid storage diseases (deficiencies of lysosomal hydrolases), if the rate of synthesis of glycosphingolipids were slowed, the burden of new incoming glycosphingolipids for breakdown in the lysosomal compartment would similarly be diminished. Any residual enzymatic activity present in the organelle would be sufficient to break down the stored glycosphingolipids in the lysosome, thus ameliorating the pathology. The goal of this therapeutic strategem was to balance the rate of biosynthesis of glycosphingolipids to their (impaired) rate of catabolism. Even in the absence of any residual enzyme activity in the lysosome, the rate at which storage material accumulated would be slowed, thereby reducing the rate at which the disease evolves. Clearly, in the absence of enzymatic activity, any prospect of arresting the progression of disease would also require a means to augment the function of the enzyme. It is critical to emphasize that the aim of this substrate reduction therapy is only partially to inhibit biosynthesis of glycosphingolipids and not block their formation completely; complete shut-off of glycosphingolipid formation would be predicted to have cytotoxic effects.2.