Date of Award
Master of Science
N. M. Ellinwood
Mucopolysaccharidosis I is a lysosomal storage disease where the lack of alpha-L-iduronidase leads to lysosomal accumulation of heparan and dermatan sulfates. This storage results in varying degrees of cardiac, skeletal, respiratory, corneal, and neural disease. Few treatments are available to patients with limited results, especially in treatment of cardiac and skeletal complications. We treated neonatal mucopolysaccharidosis I dogs with intravenous recombinant enzyme replacement therapy at the conventional 0.58 mg/kg or a higher 1.57 mg/kg weekly dose. Higher dosage led to complete normalization of lysosomal storage in liver, spleen, lung, kidney, synovium and myocardium, as well as normalization of storage in the hard-to-treat mitral valve. There was normalization of all biochemical and functional cardiac disease and striking improvements in clinical and radiographic signs of skeletal disease. In addition to somatic improvements, high and intrathecal enzyme treatment led to decreased secondary storage burden of gangliosides in the cerebral gray matter. Importantly, all animals failed to mount an antibody response to enzyme therapy, consistent with neonatal tolerization. Taken together, these findings using the canine model advocate neonatal testing and early treatment of mucopolysaccharidosis I to more completely treat cardiac and skeletal manifestations of human mucopolysaccharidosis I disease.
Ashley Dawn Dierenfeld
Dierenfeld, Ashley Dawn, "Enzyme replacement therapy treatment from birth increases therapeutic efficacy and generates tolerance to enzyme in canine mucopolysaccharidosis type I" (2009). Graduate Theses and Dissertations. 11000.