title: Bone marrow transplantation for feline mucopolysaccharidosis I.
abstract: 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 (6.3x10(7)-1.1x10(9) 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 alpha-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.
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. mellinwo@iastate.edu
authors.forename: N Matthew
authors.initials: NM
authors.lastname: Ellinwood
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Colle
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Weil
authors.forename: Margret L
authors.initials: ML
authors.lastname: Casal
authors.forename: Charles H
authors.initials: CH
authors.lastname: Vite
authors.forename: Staci
authors.initials: S
authors.lastname: Wiemelt
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Hasson
authors.forename: Thomas M
authors.initials: TM
authors.lastname: O'Malley
authors.forename: Xingxuan
authors.initials: X
authors.lastname: He
authors.forename: Ulana
authors.initials: U
authors.lastname: Prociuk
authors.forename: Lucie
authors.initials: L
authors.lastname: Verot
authors.forename: John R
authors.initials: JR
authors.lastname: Melniczek
authors.forename: Anne
authors.initials: A
authors.lastname: Lannon
authors.forename: Gustavo D
authors.initials: GD
authors.lastname: Aguirre
authors.forename: Van W
authors.initials: VW
authors.lastname: Knox
authors.forename: Sydney M
authors.initials: SM
authors.lastname: Evans
authors.forename: Marie T
authors.initials: MT
authors.lastname: Vanier
authors.forename: Edward H
authors.initials: EH
authors.lastname: Schuchman
authors.forename: Steven U
authors.initials: SU
authors.lastname: Walkley
authors.forename: Mark E
authors.initials: ME
authors.lastname: Haskins
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002415:Cats; D005260:Female; D005732:Gangliosides / Q000378:metabolism; D006025:Glycosaminoglycans / Q000378:metabolism; D006579:Heterozygote; D007068:Iduronidase / Q000378:metabolism; D008297:Male; D008059:Mucopolysaccharidosis I / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D009928:Organ Specificity
chemical_list: D005732:Gangliosides; D006025:Glycosaminoglycans; D007068:Iduronidase