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.

Cell-Mediated Immunity to NAGLU Transgene Following Intracerebral Gene Therapy in Children With Mucopolysaccharidosis Type IIIB Syndrome

“…It is caused by mutations in the a-N-acetylglucosaminidase (NAGLU) gene, coding for a lysosomal enzyme required for the stepwise degradation of heparan sulfate glycosaminoglycans (GAGs). The accumulation of incompletely degraded GAGs in affected cells and extracellular spaces leads to cognitive retardation and further neurodegeneration of the central nervous system, leading to progressive deterioration of cognitive abilities before the age of 5 years, including language acquisition delay, cognitive delay and/or abnormal behavior, and premature death in the second decade (1)(2)(3)(4). The challenge to treat MPS IIIB syndrome lies in the design of a therapy to supply the missing enzyme to the brain as early as possible after birth.…”

Electroclinical Features of Epilepsy in Mucopolysaccharidosis III: Outcome Description in a Cohort of 15 Italian Patients

“…Currently, no effective therapy is available to slow down or reverse neurodegeneration in MPS III. Different therapeutic strategies have been tested during recent years in cellular and animal models of the disease and in clinical trials ( 17 ). Symptomatic therapy is thus the mainstay of treatment to ameliorate the quality of life of patients and their relatives.…”

Splicing Modulation as a Promising Therapeutic Strategy for Lysosomal Storage Disorders: The Mucopolysaccharidoses Example

“…As previously discussed, the proper in vivo testing of splice modulation therapeutics requires the development of animal models that carry the specific splicing mutations. In fact, even though genetic models for MPSs encompass a wide range of biological systems [ 113 , 114 , 115 ] thanks to the numerous advances in mutagenesis techniques that have markedly improved the efficiency of model generation, knockout or transgenic mouse models that carry null mutations remain the gold standard within the field. It is important to notice, however, that while efforts should be made to develop suitable animal models, this may not be a straightforward task given the differences in the sequences that are involved in the overall splicing processes in different species [ 9 ].…”