HPBCD reduced the disease phenotypes in Mucopolysaccharidosis type IIIB induced pluripotent-stem-cell-derived neuronal cells

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Mucopolysaccharidoses (MPSs) are a group of lysosomal storage diseases caused by inherited deficiencies of eleven enzymes involved in the degradation of glycosaminoglycans (GAGs) such as dermatan sulfate, heparan sulfate, keratan sulfate, chondroitin sulfate or hyaluronan. Mucopolysaccharidosis type III (MPS III), also known as Sanfilippo syndrome, arises from insufficient degradation of heparan sulfate in lysosomes. There are four subtypes (A, B, C, and D) of MPS III corresponding to mutations of four different enzymes required for the catabolism of heparan sulfate. MPS IIIB is caused by pathogenic mutations in the NAGLU gene encoding α-N-acetylglucosaminidase (NAGLU). Insufficient NAGLU activity results in lysosomal accumulations of heparan sulfate. The estimated incidence of this disease is approximately 1:200,000. Neurological symptoms are predominantly clinical presentations of MPS IIIB accompanied with mild somatic manifestations. The disease usually appears in children of 2-6 years old with behavior and development problems initially followed by hyperactivity, seizures, progressive dementia, and motor disorder. There is no effective treatment or cure for MPS IIIB currently.

Deficiency in the NAGLU enzyme function and accumulation of glucoseminoglucans can further cause storages of gangliosides and other lipids that is another common feature of MPS diseases.

In this study, induced pluripotent stem cell lines were established from two MPS IIIB patient fibroblast lines and differentiated into neural stem cells and neurons. MPS IIIB neural stem cells exhibited NAGLU deficiency accompanied with glucoseaminoglucane accumulation, as well as lysosomal enlargement and secondary lipid accumulation. Treatments with recombinant NAGLU, δ-tocopherol, and 2-hydroxypropyl-b-cyclodextrin significantly reduced the disease phenotypes in these cells. The mechanism of action includes promoting lysosomal exocytosis and activation of autophagy pathway.

Huang W, Cheng YS, Yang S, Swaroop M, Xu M, Huang W, Zheng W. Disease modeling for Mucopolysaccharidosis type IIIB using patient derived induced pluripotent stem cells. Exp Cell Res. 2021, 16:112785. doi: 10.1016/j.yexcr.2021.112785.

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