Effect of high dose, repeated intra-cerebrospinal fluid injection of sulphamidase on neuropathology in mucopolysaccharidosis type IIIA mice.

Mucopolysaccharidosis type IIIA (MPS IIIA) is an inherited neurodegenerative lysosomal storage disorder characterised by progressive loss of learned skills, sleep disturbance and behavioural problems. Reduced activity of sulphamidase (SGSH; EC 3.10.1.1) results in intracellular accumulation of heparan sulphate (HS), with the brain the primary site of pathology. We have used a naturally-occurring MPS IIIA mouse model to determine the effectiveness of SGSH replacement via the cerebrospinal fluid (CSF) to decrease neuropathology. This is a potential therapeutic option for patients with this disorder. Mice received intra-CSF injections of recombinant human SGSH (30, 50 or 70 mug) fortnightly from six-18 weeks of age, and the cumulative effect on neuropathology was examined and quantified. Anti-SGSH antibodies detected in plasma at euthanasia did not appear to impact upon the health of the mice or the experimental outcome, with significant, but region- and dose-dependent reductions in an HS-derived oligosaccharide observed in the brain and spinal cord using tandem mass spectrometry. SGSH infusion reduced the number of storage inclusions observed in the brain when visualised using electron microscopy and this correlated with a significant decrease in the immunohistochemical staining of a lysosomal membrane marker (LIMP-II). Reduced numbers of activated isolectin-B4-positive microglia and GFAP-positive astrocytes were seen in many, but not all, brain regions. Significant reductions in the number of ubiquitin-positive intracellular inclusions were also observed. These outcomes demonstrate the effectiveness of this method of enzyme delivery in reducing the spectrum of neuropathological changes in murine MPS IIIA brain.