Specific antibody titer alters the effectiveness of intrathecal enzyme replacement therapy in canine mucopolysaccharidosis I

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.

► MPS I dogs may develop antibodies against intrathecal enzyme replacement therapy.
► We studied the brains of these dogs using a pGAG assay.
► We detected higher pGAG in brains of treated dogs with higher antibody titers.
► We detected a 69% reduction in pGAG in cerebrospinal fluid of treated dogs.