Lysosomal storage disorders (LSD) are rare inherited metabolic diseases in which genetic alterations affect lysosomal proteins. Mucopolysaccharidosis type IIIA (MPS-IIIA) is an LSD characterized by reduced activity of sulfamidase (heparan-N-sulfatase, EC22.214.171.124), which degrades the sulfated glycosoaminoglycan heparan sulfate. The central nervous system (CNS) is the main site of pathology in MPS-IIIA, resulting in reduced neurological function and neurocognitive decline. Neuropathological changes include lysosomal vacuolation of heparan sulfate and lipids in neurons, glia, and perivascular cells and the formation of axonal spheroids and ectopic dendrites. At present there is no effective treatment for the CNS effects of LSD as enzyme administered intravenously cannot cross the blood-brain barrier. We have previously established and characterized a mouse model of MPS-IIIA, and in the present study, we injected recombinant human sulfamidase directly into the brain at 6, 12 or 18 weeks of age. Treatment reduced vacuolation and gliosis and delayed the onset of ubiquitin-positive neurodegenerative changes in widespread areas of MPS-IIIA brain, assessed at 24 weeks of age. However, ubiquitin-positive axonal spheroids already detectable by 6 weeks of age were unaffected by treatment at any age, suggesting their irreversibility and thus indicating the importance of early detection of MPS-IIIA and instigation of therapy.
- Lysosomal storage disorder