title: Enzyme replacement improves ataxic gait and central nervous system histopathology in a mouse model of metachromatic leukodystrophy.
abstract: Inherited deficiencies of lysosomal hydrolases cause lysosomal storage diseases (LSDs) that are characterized by a progressive multisystemic pathology and premature death. Repeated intravenous injection of the active counterpart of the deficient enzyme, a treatment strategy called enzyme replacement therapy (ERT), evolved as a clinical option for several LSDs without central nervous system (CNS) involvement. To assess the efficacy of long-term ERT in metachromatic leukodystrophy (MLD), an LSD with prevailing nervous system disease, we treated immunotolerant arylsulfatase A (ASA) knockout mice with 52 doses of either 4 or 50 mg/kg recombinant human ASA (rhASA). ERT was tolerated without side effects and improved disease manifestations in a dose-dependent manner. Dosing of 4 mg/kg diminished sulfatide storage in kidney and peripheral nervous system (PNS) but not the CNS, whereas treatment with 50 mg/kg was also effective in the CNS in reducing storage in brain and spinal cord by 34 and 45%, respectively. Histological analyses revealed regional differences in sulfatide clearance. While 70% less storage profiles were detectable, for example, in the hippocampal fimbria, the histopathology of the brain stem was unchanged. Both enzyme doses normalized the ataxic gait of ASA knockout mice, demonstrating prevention of nervous system dysfunctions that dominate early stages of MLD.
authors.affiliation: Institut für Physiologische Chemie, Rheinische Friedrich-Wilhelms-Universität, Bonn, Germany. matzner@institut.physiochem.uni-bonn.de
authors.forename: Ulrich
authors.initials: U
authors.lastname: Matzner
authors.forename: Renate
authors.initials: R
authors.lastname: Lüllmann-Rauch
authors.forename: Stijn
authors.initials: S
authors.lastname: Stroobants
authors.forename: Claes
authors.initials: C
authors.lastname: Andersson
authors.forename: Cecilia
authors.initials: C
authors.lastname: Weigelt
authors.forename: Carl
authors.initials: C
authors.lastname: Eistrup
authors.forename: Jens
authors.initials: J
authors.lastname: Fogh
authors.forename: Rudi
authors.initials: R
authors.lastname: D'Hooge
authors.forename: Volkmar
authors.initials: V
authors.lastname: Gieselmann
mesh_terms: D000818:Animals; D001259:Ataxia / Q000503:physiopathology / Q000628:therapy*; D001522:Behavior, Animal; D002490:Central Nervous System / Q000473:pathology*; D002553:Cerebroside-Sulfatase / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005684:Gait; D006801:Humans; D007966:Leukodystrophy, Metachromatic / Q000628:therapy*; D051379:Mice; D018345:Mice, Knockout; D011994:Recombinant Proteins / Q000627:therapeutic use
chemical_list: D011994:Recombinant Proteins; D002553:Cerebroside-Sulfatase