Sanfilippo Syndrome: Molecular Basis, Disease Models and Therapeutic Approaches

Abstract

Sanfilippo syndrome or mucopolysaccharidosis III is a lysosomal storage disorder caused by mutations in genes responsible for the degradation of heparan sulfate, a glycosaminoglycan located in the extracellular membrane. Undegraded heparan sulfate molecules accumulate within lysosomes leading to cellular dysfunction and pathology in several organs, with severe central nervous system degeneration as the main phenotypical feature. The exact molecular and cellular mechanisms by which impaired degradation and storage lead to cellular dysfunction and neuronal degeneration are still not fully understood. Here, we compile the knowledge on this issue and review all available animal and cellular models that can be used to contribute to increase our understanding of Sanfilippo syndrome disease mechanisms. Moreover, we provide an update in advances regarding the different and most successful therapeutic approaches that are currently under study to treat Sanfilippo syndrome patients and discuss the potential of new tools such as induced pluripotent stem cells to be used for disease modeling and therapy development.

Keywords: Sanfilippo syndrome; animal models; cellular models; heparan sulfate; induced pluripotent stem cells; lysosomal storage disorders; mucopolysaccharidosis III; therapeutic approaches.

Figure 1

Synthesis and degradation of heparan sulfate (HS). Schematic representation of the biosynthesis and degradation processes of HS, including organelle location of each step, enzymes responsible for each function, residues in the HS chains, and modifications of these residues. GAGs—glycosaminoglycans.

Figure 2

Potential therapeutic approaches to treat Sanfilippo syndrome. Schematic representation of the main therapeutic strategies currently being studied for the treatment of Sanfilippo syndrome patients: enzyme replacement therapy to provide the correct form of the mutated protein (A), substrate reduction therapy to reduce storage of undegraded molecules (B), use of pharmacological chaperones to correct protein missfolding (C), stem cell therapy for regeneration and production of the correct form of the protein (D) and gene therapy to provide cells with the correct form of the mutated gene (E).