ABSTRACT
Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disease caused by loss of activity of α-l-iduronidase and attendant accumulation of the glycosaminoglycans dermatan sulfate and heparan sulfate. Current treatments are suboptimal and do not address residual disease including corneal clouding, skeletal deformities, valvular heart disease, and cognitive impairment. We treated neonatal dogs with MPS I with intravenous recombinant α-l-iduronidase replacement therapy at the conventional 0.58 mg/kg or a higher 1.57 mg/kg weekly dose for 56 to 81 weeks. In contrast to previous results in animals and patients treated at a later age, the dogs failed to mount an antibody response to enzyme therapy, consistent with the induction of immune tolerance in neonates. The higher dose of enzyme led to complete normalization of lysosomal storage in the liver, spleen, lung, kidney, synovium, and myocardium, as well as in the hard-to-treat mitral valve. Cardiac biochemistry and function were restored, and there were improvements in skeletal disease as shown by clinical and radiographic assessments. Glycosaminoglycan levels in the brain were normalized after intravenous enzyme therapy, in the presence or absence of intrathecal administration of recombinant α-l-iduronidase. Histopathological evidence of glycosaminoglycan storage in the brain was ameliorated with the higher-dose intravenous therapy and was further improved by combining intravenous and intrathecal therapy. These findings argue that neonatal testing and early treatment of patients with MPS I may more effectively treat this disease.
Subject(s)
Enzyme Therapy , Iduronidase/administration & dosage , Iduronidase/therapeutic use , Mucopolysaccharidosis I/therapy , Animals , Animals, Newborn , Bone and Bones/pathology , Brain/metabolism , Brain/pathology , Dogs , Glycosaminoglycans/metabolism , Humans , Iduronidase/genetics , Joints/pathology , Lysosomes/metabolism , Mucopolysaccharidosis I/pathology , Mucopolysaccharidosis I/physiopathology , Tissue DistributionABSTRACT
The outcome of the project reported on here is a client-centered consumer satisfaction questionnaire designed to evaluate new models of residential continuing care in Alberta, Canada. Satisfaction is defined as a multi-dimensional construct that is grounded in the consumer's experience. Consultation with the clients of the services during development of the instrument ensured that characteristics important to the clients were assessed. The result is an instrument with which to measure satisfaction that is fully client-centered and that, with appropriate modifications, can be used to monitor any client-centered program for cognitively-able continuing care clients.
