Caprine mucopolysaccharidosis IIID - A preliminary trial of enzyme replacement therapy

Mucopolysaccharidosis type IIID (MPS IIID) is a lysosomal storage disorder resulting from lack of activity of the lysosomal hydrolase N-acetylglucosam ine 6-sulfatase (6S) (EC 3.1.6.14). The syndrome is associated with systemi c and central nervous system (CNS) heparan sulfate glycosaminoglycan (HS-GA G) accumulation, secondary storage of lipids, and severe, progressive demen tia. In this investigation, caprine MPS IIID, established as a large animal model for the human disease, was used to evaluate the efficacy of enzyme r eplacement therapy (ERT). Recombinant caprine 6S (rc6S) (1 mg/kg/dose) was administered intravenously to one MPS IIID goat kid at 2, 3, and 4 wks of a ge. Five days after the last dose, the uronic acid (UA) content and the com position of uncatabolized MS-GAG fractions in the brain of the ERT-treated MPS IIID kid were similar to those from a control, untreated MPS IIID anima l. However, hepatic uronic acid levels in the treated MPS IIID kid were app roximately 90% lower than those in the untreated MPS IIID control; whereas the composition of the residual hepatic MS-GAG was identical to that in the untreated animal. Marked reduction of lysosomal storage vacuoles in hepati c cells of the treated MPS IIID kid was observed, but ERT had no effect on CNS lesions. No residual 6S activity was detected in brain or liver. This p reliminary investigation indicates that other treatment regimens will be ne cessary to ameliorate MPS III-related CNS lesions.