Degree Type

Thesis

Date of Award

2009

Degree Name

Master of Science

Department

Animal Science

First Advisor

N. M. Ellinwood

Abstract

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.

Copyright Owner

Ashley Dawn Dierenfeld

Language

en

Date Available

2012-04-30

File Format

application/pdf

File Size

83 pages

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