TY - JOUR
T1 - Bone marrow transplantation for feline mucopolysaccharidosis I
AU - Ellinwood, N. Matthew
AU - Colle, Marie Anne
AU - Weil, Margaret A.
AU - Casal, Margret L.
AU - Vite, Charles H.
AU - Wiemelt, Staci
AU - Hasson, Christopher W.
AU - O'Malley, Thomas M.
AU - He, Xingxuan
AU - Prociuk, Ulana
AU - Verot, Lucie
AU - Melniczek, John R.
AU - Lannon, Anne
AU - Aguirre, Gustavo D.
AU - Knox, Van W.
AU - Evans, Sydney M.
AU - Vanier, Marie T.
AU - Schuchman, Edward H.
AU - Walkley, Steven U.
AU - Haskins, Mark E.
N1 - Funding Information:
Appreciation is extended to Pat Miller-Wilson for irradiation, and to veterinary students for compassionate animal care. Supported by NIH: DK025759 and RR02512 (MEH), NME supported by RR007063.
PY - 2007/7
Y1 - 2007/7
N2 - 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.
AB - 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.
KW - Bone marrow transplantation
KW - Disease models, animal
KW - Glycosaminoglycans
KW - Iduronidase
KW - Lysosomal storage diseases
KW - Mucopolysaccharidosis I
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UR - http://www.scopus.com/inward/citedby.url?scp=34249305165&partnerID=8YFLogxK
U2 - 10.1016/j.ymgme.2007.03.001
DO - 10.1016/j.ymgme.2007.03.001
M3 - Article
C2 - 17482862
AN - SCOPUS:34249305165
SN - 1096-7192
VL - 91
SP - 239
EP - 250
JO - Molecular Genetics and Metabolism
JF - Molecular Genetics and Metabolism
IS - 3
ER -
