Replacing the Enzyme α-l-Iduronidase at Birth Ameliorates Symptoms in the Brain and Periphery of Dogs with Mucopolysaccharidosis Type I

Replacing the enzyme α-l-iduronidase at birth ameliorates symptoms in the brain and periphery of dogs with mucopolysaccharidosis type I. When Dogs Really Are Man’s Best Friend For certain diseases, dogs provide an excellent large-animal model and the lysosomal storage disorder mucopolysaccharidosis type I is no exception. In this disease, a defect in the enzyme α-l-iduronidase prevents breakdown of glycosaminoglycans, resulting in their accumulation in the lysosomes of cells, leading to engorged and dysfunctional cells. A variety of serious complications ensue such as enlarged organs, skeletal defects, corneal clouding, abnormal heart valves, and cognitive deficits. Although a human recombinant form of the enzyme has proved successful in treating patients with less severe forms of the disease, only some of the symptoms are ameliorated and patients often develop antibodies to the enzyme. Dierenfeld and colleagues reasoned that starting enzyme replacement therapy at birth could halt or even reverse the more serious disease symptoms such as heart valve defects, skeletal deformities, and cognitive impairment and might prevent antibodies from forming against human recombinant α-l-iduronidase. Working in a naturally occurring dog model of mucopolysaccharidosis type I in which the animals have a defective α-l-iduronidase enzyme and show most of the symptoms of the human disease, Dierenfeld et al. administered two different doses of α-l-iduronidase (0.58 and 1.57 mg/kg) intravenously every week starting a few days after birth. The authors show that starting enzyme replacement therapy at such a young age prevented the formation of antibodies against the enzyme due to neonatal immune tolerance. Treated dogs showed marked reductions in glycosaminoglycans in a variety of different tissues including the mitral heart valve, which has been refractory to traditional enzyme treatment administered at later ages. Furthermore, treated dogs showed relatively normal skeletons and lacked the stiff gait, lax joints, upturned nose, and poor neck flexibility exhibited by untreated animals with the disease. Compellingly, glycosaminoglycan levels and cortical atrophy in the brain decreased and corneal clouding improved slightly (at the higher dose) in the treated dogs. These results show that starting intravenous administration of α-l-iduronidase at higher doses and as soon as possible after birth increases the efficacy of enzyme replacement therapy and ensures immune tolerance to the enzyme. These promising results in man’s best friend suggest that children with severe mucopolysaccharidosis type I or other early-onset lysosomal storage diseases should start enzyme replacement therapy as soon as possible after birth. 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.