Mucopolysaccharidosis IIIA is a hereditary disease caused by mutations in the sulfamidase enzyme that participates in catabolism of heparan sulfate (HS), leading to HS fragment accumulation and multisystemic failure. No cure exists and death occurs around the second decade of life. Two low molecular weight highly sulfated compounds derived from marine diabolican and infernan exopolysaccharides (A5_3 and A5_4, respectively) with heparanase inhibiting properties were tested in a MPSIIIA cell line model, resulting in limited degradation of intracellular HS. Next, we observed the effects of intraperitoneal injections of the diabolican derivative A5_3 from 4 to 12 weeks of age on MPSIIIA mice. Brain metabolism and microstructure, levels of proteins and genes involved in MPSIIIA brain pathophysiology were also investigated. ¹H-Magnetic Resonance Spectroscopy (MRS) indicated deficits in energetic metabolism, tissue integrity and neurotransmission at both 4 and 12 weeks in MPSIIIA mice, with partial protective effects of A5_3. Ex-vivo Diffusion Tensor Imaging (DTI) showed white matter microstructural damage in MPSIIIA, with noticeable protective effects of A5_3. Protein and gene expression assessments displayed both pro-inflammatory and pro-apoptotic profiles in MPSIIIA mice, with benefits of A5_3 counteracting neuroinflammation. Overall, derivative A5_3 was well tolerated and was shown to be efficient in preventing brain metabolism failure and inflammation, resulting in preserved brain microstructure in the context of MPSIIIA.

This review comes as a part of the special issue “Emerging frontiers in GAGs and mimetics”. Our interest is in the manipulation of heparan sulfate (HS) turnover by employing HS mimetics/heparin derivatives that exert pleiotropic effects and are interesting for interfering at multiple levels with pathways in which HS is implicated. Due to the important role of heparanase in HS post-biosynthetic modification and catabolism, we focus on the possibility to target heparanase, at both extracellular and intracellular levels, a strategy that can be applied to many conditions, from inflammation to cancer and neurodegeneration.

To evaluate a new approach to Mucopolysaccharidosis type IIIA (MPS-IIIA), work was initiated on primary fibroblasts from a well-known mouse model in which sulfamidase deficiency correlates with the accumulation of heparan sulfate - the hallmark of this disease. Once the culture of fibroblasts was established, we observed continuous proliferation with a rapid growth rate, loss of contact inhibition and late passage stability, corresponding to a spontaneously immortalized cell line. The presence of the single point D31N mutation was verified and both rapid and abundant intracellular accumulation of low molecular weight HS was observed, confirming both genotype and phenotype. This cell line is a potential in vitro model system for future studies of MPS-IIIA prior to employing animal models.