LONG-TERM AND HIGH-DOSE TRIALS OF ENZYME REPLACEMENT THERAPY IN THE CANINE MODEL OF MUCOPOLYSACCHARIDOSIS

Enzyme replacement is a potential therapy for mucopolysaccharidosis I( MPS I), a lysosomal storage disorder caused by alpha-L-iduronidase def iciency. Previous work showed improvement in the tissues of MIPS I dog s treated intravenously for 3 months with recombinant human alpha-L-id uronidase (25,000 units or similar to 0.1 mg/kg/week). We have now tre ated an MPS I-affected dog for 13 months to assess the clinical effect s of enzyme replacement. The treated dog gained more weight, was more active, and had less joint stiffness than the untreated littermate. Bi ochemical and histologic studies demonstrated uptake of alpha-L-iduron idase and decreased lysosomal storage in the liver, kidney, spleen, ly mph nodes, synovium, adrenals, and lungs. The brain had detectable enz yme activity and decreased glycosaminoglycan storage although histolog ic improvement was not evident. Cartilage and heart valve did not show any detectable improvement. A fivefold higher dose (similar to 0.5 mg /kg) administered five times over 10 days to two other dogs resulted i n higher tissue enzyme activity and similarly decreased glycosaminogly can storage and excretion. Antibodies to human alpha-L-iduronidase wer e induced in all treated dogs lad may be associated with immune comple x deposition and proteinuria. Recombinant canine alpha-L-iduronidase a lso induced antibody formation to a similar degree. The results suppor t the conclusion that enzyme replacement is a premising therapy for MP S I though immunologic complications may occur. (C) 1996 Academic Pres s, Inc.