Injection of recombinant human sulfamidase into the CSF via the cerebellomedullary cistern in MPS IIIA mice.

At present, there is no widely available, safe and effective treatment for lysosomal storage disorders (LSD) that affect the brain. We have used a naturally occurring mouse model of mucopolysaccharidosis type IIIA (MPS IIIA) or Sanfilippo syndrome, to evaluate the effect of repeated injection of recombinant human sulfamidase (rhSGSH) into the cerebrospinal fluid via the cisterna magna (CM) on central nervous system (CNS) pathology and behavioral function. Mice received up to seven injections of rhSGSH (5-20 microg rhSGSH per injection) or vehicle on a fortnightly or monthly basis. A dose-dependent reduction in the level of a heparan sulfate-derived monosulfated disaccharide was observed within the brain (up to 62% reduction compared with vehicle-treated MPS IIIA mice) and spinal cord (up to 71% reduction). Ultrastructural examination revealed a reduction in lysosomal vesicle formation in various cell types and fewer (ubiquitin-positive) axonal spheroids were observed in several brain regions. The biochemical changes were accompanied by improved behavior, particularly in mice-treated more frequently. A humoral immune response to rhSGSH was observed in treated animals. Intra-CM injection of lysosomal enzyme may therefore represent an immediately applicable method of treating the CNS effects of this and potentially other LSD that affect the brain.