Mucopolysaccharidosis IIIA (
MPS IIIA or Sanfilippo disease) is a
neurodegenerative disorder caused by a deficiency in the lysosomal
enzyme sulfamidase (SGSH), catabolizing
heparan sulfate (HS). Affected children present with severe behavioral abnormalities, sleep disturbances, and progressive neurodegeneration, leading to death in their second decade. MPS I, a similar
neurodegenerative disease accumulating HS, is treated successfully with
hematopoietic stem cell transplantation (HSCT) but this treatment is ineffectual for
MPS IIIA. We compared HSCT in
MPS IIIA mice using wild-type donor cells transduced ex vivo with lentiviral vector-expressing SGSH (LV-WT-HSCT) versus wild-type donor cell transplant (WT-HSCT) or lentiviral-SGSH transduced
MPS IIIA cells (LV-IIIA-HSCT). LV-WT-HSCT results in 10% of normal brain
enzyme activity, near normalization of brain HS and GM2
gangliosides, significant improvements in
neuroinflammation and behavioral correction. Both WT-HSCT and LV-IIIA-HSCT mediated improvements in GM2
gangliosides and
neuroinflammation but were less effective at reducing HS or in ameliorating abnormal HS sulfation and had no significant effect on behavior. This suggests that HS may have a more significant role in neuropathology than
neuroinflammation or GM2
gangliosides. These data provide compelling evidence for the efficacy of gene therapy in conjunction with WT-HSCT for neurological correction of
MPS IIIA where conventional transplant is ineffectual.