Sanfilippo type C disease: pathogenic mechanism and potential therapeutic applications

Abstract

ABSTRACTIntroduction: A rare orphan disorder, Mucopolysaccharidosis III type C (MPS IIIC) is caused by mutations in the HGSNAT (heparan sulfate acetyl-CoA:α-glucosaminide N-acetyltransferase) gene resulting in lysosomal storage of heparan sulfate (HS). In the brain, HS accumulation triggers neuronal death leading to neuropsychiatric problems, mental retardation, and dementia.Areas covered: The review describes the discovery of lysosomal transmembrane acetylation and its deficiency in MPS IIIC, identification of the causative gene and mutations in the patients and the analysis of pathophysiological mechanism in the mouse models of the disease. These studies have shown that storage of HS in the microglial cells and their activation triggers neuroinflammation and neuronal death. Many MPS IIIC patients have missense mutations resulting in the synthesis of misfolded protein and partially amendable by pharmacological chaperons. In the mouse model disease can be prevented by supraphysiological delivery of wild-type HGSNAT via AAV-mediated gene transfer.Expert opinion: The recent advances in understanding the disease pathology and preclinical research suggest that treatment for MPS IIIC can be developed by using two orthogonal strategies: (1) gene/cell therapy and (2) chaperone therapy to restore folding of HGSNAT missense mutants. Importantly, both approaches could be used together to increase the probability of success.