Less Is More: Substrate Reduction Therapy for Lysosomal Storage Disorders

Abstract

Lysosomal storage diseases (LSDs) are a group of rare, life-threatening genetic disorders, usually caused by a dysfunction in one of the many enzymes responsible for intralysosomal digestion. Even though no cure is available for any LSD, a few treatment strategies do exist. Traditionally, efforts have been mainly targeting the functional loss of the enzyme, by injection of a recombinant formulation, in a process called enzyme replacement therapy (ERT), with no impact on neuropathology. This ineffectiveness, together with its high cost and lifelong dependence is amongst the main reasons why additional therapeutic approaches are being (and have to be) investigated: chaperone therapy; gene enhancement; gene therapy; and, alternatively, substrate reduction therapy (SRT), whose aim is to prevent storage not by correcting the original enzymatic defect but, instead, by decreasing the levels of biosynthesis of the accumulating substrate(s). Here we review the concept of substrate reduction, highlighting the major breakthroughs in the field and discussing the future of SRT, not only as a monotherapy but also, especially, as complementary approach for LSDs.

Keywords: Gaucher disease (GD); Niemann-Pick type C (NPC); Sanfilippo syndrome); combination therapy; eligluistat tartrate; genistein; miglustat; mucopolysaccharidosis type III (MPS III; substrate reduction therapy (SRT).

Figure 1

Schematic presentation of the Glycosphingolipids (GLS) biosynthesis, emphasizing the conversion of ceramide to glucosylceramide (GlcCer) via the action of UDP-glucose:N-acylsphingosine glucosyltransferase (ceramide glucosyltransferase, CGT), major target for substrate reduction approaches in GLS-storage diseases (*) (Adapted from [26]).

Figure 2

Schematic presentation of the biosynthetic assembly of heparan sulfate (HS) and heparin (Hep) from GAG backbones through the action of several glycosyltransferases (adapted from [106]). Each glycosyltransferase requires the respective UDP-sugar as a donor substrate. Following the synthesis of specific core proteins, the synthesis of the so-called GAG-protein linkage region, GlcUA β1—3Gal β1—3Gal β1—4Xylβ1-O-, common to chondroitin sulfate/dermatan sulfate (CS/DS) and HS/Hep chains, is initiated by XylT, which transfers a Xyl residue from UDP-Xyl to the specific Ser residue in the endoplasmic reticulum, and is completed by the consecutive addition of each sugar by GalT-I, GalT-II, and GlcAT-I, which are common to the biosynthesis of both CS and HS, in the Golgi apparatus. The addition of 1–4-linked GlcNAc to the linkage region by GlcNAcT-I initiates the assembly of the HS repeating disaccharide region, (-4GlcNAcβ1—4GlcUAβ1-)_n. Then, the chain polymerization of the HS chain is catalyzed by HS-GlcAT-II and GlcNAcT-II activities of HS polymerase, which is a heterocomplex of EXT1 and EXT2. After the formation of the heparan backbone, GAG chains are matured by sulfation at various positions and epimerization at GlcUA residues. Each enzyme (glycosyltransferase and/or epimerase) is described by its respective sugar symbol: β-xylosyltransferase (XylT); β-1,4-galactosyltransferase-I (GalT-I); β-1,3-galactosyltransferase-II (GalT-II); β-1,3-glucuronosyltransferases (GlcAT-I and GlcAT-II); and 1,4-N-acetylglucosaminyltransferase (GlcNAcT-I). Sulfotransferases involved in the chain modifications are not included.