Date of this Version
Molecular Genetics and Metabolism
Severe mucopolysaccharidosis type I (MPS I) is a fatal neuropathic lysosomal storage disorder with significant skeletal involvement. Treatment involves bone marrow transplantation (BMT), and although effective, is suboptimal, due to treatment sequelae and residual disease. Improved approaches will need to be tested in animal models and compared to BMT. Herein we report on bone marrow transplantation to treat feline mucopolysaccharidosis I (MPS I). Five MPS I stably engrafted kittens, transplanted with unfractionated bone marrow (6.3 × 107–1.1 × 109 nucleated bone marrow cells per kilogram) were monitored for 13–37 months post-engraftment. The tissue total glycosaminoglycan (GAG) content was reduced to normal levels in liver, spleen, kidney, heart muscle, lung, and thyroid. Aorta GAG content was between normal and affected levels. Treated cats had a significant decrease in the brain GAG levels relative to untreated MPS I cats and a paradoxical decrease relative to normal cats. The α-l-iduronidase (IDUA) activity in the livers and spleens of transplanted MPS I cats approached heterozygote levels. In kidney cortex, aorta, heart muscle, and cerebrum, there were decreases in GAG without significant increases in detectable IDUA activity. Treated animals had improved mobility and decreased radiographic signs of disease. However, significant pathology remained, especially in the cervical spine. Corneal clouding appeared improved in some animals. Immunohistochemical and biochemical analysis documented decreased central nervous system ganglioside storage. This large animal MPS I study will serve as a benchmark of future therapies designed to improve on BMT.
NOTICE: This is the author’s version of a work that was accepted for publication in Molecular Genetics and Metabolism. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms, may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Molecular Genetics and Metabolism, 91, 3, 10.1016/j.ymgme.2007.03.001.
bone marrow transplantation, disease models, animal, lysosomal storage diseases, iduronidase, glycosaminoglycans, mucopolysaccharidosis I
Ellinwood, N., Colle, M., Weil, M. A., Casal, M. L., Vite, C. H., Wiemelt, S., Hasson, C. W., O'Malley, T. M., He, X., Prociuk, U., Verot, L., Melniczek, J. R., Lannon, A., Aguirre, G. D., Knox, V. W., Evans, S. M., Vanier, M. T., Schuchman, E. H., Walkley, S. U., & Haskins, M. E. (2007). Bone Marrow Transplantation for Feline Mucopolysaccharidosis I. Molecular Genetics and Metabolism, 91 (3), 239-250. http://dx.doi.org/10.1016/j.ymgme.2007.03.001
Date Posted: 06 May 2015
This document has been peer reviewed.