Quantitative Evaluation of Bones in Murine MPS VII After Replacement Therapy Using Chemically Modified Enzyme

Abstract

Mucopolysaccharidosis type VII is a lysosomal storage disease caused by deficiency of lysosomal beta-glucuronidase, which participates in degradation of glycosaminoglycans. Glycosaminoglycans storage in mucopolysaccharidosis type VII causes a wide spectrum of clinical manifestations that affect the central nervous system, bone, and viscera. Enzyme replacement therapy effectively clears storage in viscera. However, clearance of storage in central nervous system is limited by the blood brain barrier. Nonetheless, recent studies showed that a chemically modified form of beta-glucuronidase, called PerT-GUS, reduced central nervous system storage. Although clearance of storage in cartilage is also limited by the avascularity of the articular surface and growth plate, prior work showed improvement of skeletal disease in mucopolysaccharidosis type VII mice treated from birth with native beta-glucuronidase. To evaluate the effectiveness of PerT-GUS in reducing the skeletal pathology, we treated mucopolysaccharidosis type VII mice from birth with PerTGUS. Micro-CT and X-rays demonstrated marked improvements in bone lesions of legs, ribs, and spine of treated mice. Quantitative histopathological assay revealed improvements in glycosaminoglycan storage and in morphology of articular and epiphyseal cartilage. Thus, PerT-GUS therapy from birth, like treatment with native betaglucuronidase, may reduce disability caused by bone dysplasia in addition to addressing central nervous system storage.