Targeting Heparan Sulfate Proteoglycans as a Novel Therapeutic Strategy for Mucopolysaccharidoses

Abstract

Mucopolysaccharidoses (MPSs) are inherited metabolic diseases caused by the deficiency of lysosomal enzymes needed to catabolize glycosaminoglycans (GAGs). Four therapeutic options are currently considered: enzyme replacement therapy, substrate reduction therapy, gene therapy, and hematopoietic stem cell transplantation. However, while some of them exhibit limited clinical efficacy and require high costs, others are still in development. Therefore, alternative treatments for MPSs need to be explored. Here we describe an innovative therapeutic approach based on the use of a recombinant protein that is able to bind the excess of extracellular accumulated heparan sulfate (HS). We demonstrate that this protein is able to reduce lysosomal defects in primary fibroblasts from MPS I and MPS IIIB patients. We also show that, by masking the excess of extracellular accumulated HS in MPS fibroblasts, fibroblast growth factor (FGF) signal transduction can be positively modulated. We, therefore, suggest the use of a competitive binding molecule for HS in MPSs as an alternative strategy to prevent the detrimental extracellular substrate storage.

Heparan Sulfate Proteoglycan Signaling in Tumor Microenvironment

“…Specific domains of proteoglycan core and/or HS chains as well as HSPG synthetizing and remodeling enzymes represent potential therapeutic targets [205]. Among the explored approaches, there is the use of high-affinity antibodies recognizing functional epitopes of HSPGs, HS mimetic compounds, cationic proteins which interact with the highly anionic sulfate and carboxylate moieties of HS chains, natural and synthetic peptides, small organic molecules that may affect either HSPG-protein interactions and subsequent signaling or the HSPG biosynthetic machinery [4][5][6]29,32,37,155,156,165,[239][240][241][242][243]. Some examples of HSPG targeting-based therapeutics for cancer treatment are reported in Table 4.…”

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

“…In MPSs, the lysosomal accumulation of undigested GAGs is considered the "primum movens" of the subsequent functional cell impairment; however, evidence demonstrates that the accumulation of storage material does not occur only in the lysosomes, but also on the cell surface and ECM where GAGs form proteoglycans through their covalent binding to a core protein [105,106,109]. The accumulation of storage material in non-lysosomal compartments accounts for impaired cell signaling and trafficking, protein unfolding, abnormal autophagy, alterations of intracellular calcium homeostasis, lysolipid accumulation, and modifications in other cellular processes that ultimately lead to the MPS phenotypes [150][151][152][153][154][155][156][157][158][159].…”

The Challenge of Modulating Heparan Sulfate Turnover by Multitarget Heparin Derivatives

“…De Pasquale et al recently published an innovative approach called substrate-masking technology based on sequestering of extracellular excess HS (and/or DS) with consequent restoring of the natural equilibrium. Treatment of primary fibroblasts from MPS IIIA-and MPS IIIB-patients with the protein NK1 resulted in decreased GAGs accumulation and restoration of FGF2 signaling [110].…”