Intrathecal
enzyme replacement therapy is an experimental option to treat
central nervous system disease due to lysosomal storage. Previous work shows that MPS I dogs receiving
enzyme replacement with recombinant human
alpha-l-iduronidase into the cisterna magna showed normal brain
glycosaminoglycan (GAG) storage after three or four doses. We analyzed MPS I dogs that received intrathecal
enzyme in a previous study using an assay that detects only pathologic GAG (
pGAG). To quantify
pGAG in MPS I, the assay measures only those GAG which display terminal
iduronic acid residues on their non-reducing ends. Mean cortical brain
pGAG in six untreated MPS I dogs was 60.9±5.93 pmol/mg wet weight, and was 3.83±2.64 in eight normal or unaffected carrier animals (p<0.001). Intrathecal
enzyme replacement significantly reduced
pGAG storage in all treated animals. Dogs with low anti-
iduronidase antibody titers showed normalization or near-normalization of
pGAG in the brain (mean 8.17±6.17, n=7), while in dogs with higher titers,
pGAG was reduced but not normal (mean 21.9±6.02, n=4). Intrathecal
enzyme therapy also led to a mean 69% reduction in cerebrospinal fluid
pGAG (from 83.8±26.3 to 27.2±12.3 pmol/ml CSF). The effect was measurable one month after each dose and did not differ with antibody titer. Prevention of the immune response to
enzyme may improve the efficacy of intrathecal
enzyme replacement therapy for
brain disease due to MPS I.