title: The effects of intracisternal enzyme replacement versus sham treatment on central neuropathology in preclinical canine fucosidosis.
abstract: BACKGROUND
  Fucosidosis results from lack of α-L-fucosidase activity, with accumulation of fucose-linked substrates in the nervous system and viscera leading to progressive motor and mental deterioration, and death. The naturally occurring dog model of fucosidosis was used to evaluate the neuropathological responses to partial enzyme replacement, and substrate reduction in early disease following treatment with recombinant canine α-L-fucosidase delivered through cerebrospinal fluid.
  
  
  METHODS
  Neuropathology in both treated (n = 3) and untreated fucosidosis-affected (n = 3) animals was evaluated with immunohistochemistry, image analysis, manual quantification and gene expression analysis and compared with unaffected age-matched controls (n = 3) in an extension of our previous biochemical report on the same cohort. Data were analyzed by ANOVA.
  
  
  RESULTS
  Quantification demonstrated a consistent trend to reduction in vacuolation, pyramidal neuron loss, astrocytosis, microgliosis, perivascular storage, apoptosis, oligodendrocyte loss, and hypomyelination throughout the central nervous system of enzyme treated animals compared to placebo-treated, age-matched affected controls. Key lesions including lysosomal expansion in neurons of deep cortex, astrocytosis in cerebral cortex and medulla, and increased lysosomal membrane associated protein-1 (LAMP-1) gene expression were ameliorated in treated animals. There was no change in spheroid formation and loss of Purkinje cells, but Purkinje cell vulnerability to apoptosis was reduced with treatment.
  
  
  CONCLUSIONS
  Despite reduced severity of fucosidosis neuropathology with partial enzyme replacement, more complete and sustained biochemical correction is required to halt neuropathological processes in this large animal model of lysosomal storage disease.
authors.affiliation: Faculty of Veterinary Science, University of Sydney, Camperdown, NSW, 2006, Australia.
authors.forename: Gauthami Sudhamayee
authors.initials: GS
authors.lastname: Kondagari
authors.affiliation: Faculty of Veterinary Science, University of Sydney, Camperdown, NSW, 2006, Australia.
authors.forename: Jessica Louise
authors.initials: JL
authors.lastname: Fletcher
authors.affiliation: Faculty of Veterinary Science, University of Sydney, Camperdown, NSW, 2006, Australia.
authors.forename: Rachel
authors.initials: R
authors.lastname: Cruz
authors.affiliation: Faculty of Veterinary Science, University of Sydney, Camperdown, NSW, 2006, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Williamson
authors.affiliation: Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, Adelaide, SA, 5000, Australia.
authors.forename: John J
authors.initials: JJ
authors.lastname: Hopwood
authors.affiliation: Faculty of Veterinary Science, University of Sydney, Camperdown, NSW, 2006, Australia. rosanne.taylor@sydney.edu.au.
authors.forename: Rosanne Maree
authors.initials: RM
authors.lastname: Taylor
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000473:pathology*; D002946:Cisterna Magna; D004195:Disease Models, Animal; D004285:Dogs; D005645:Fucosidosis / Q000188:drug therapy* / Q000473:pathology*; D060186:Infusions, Spinal; D016896:Treatment Outcome; D005644:alpha-L-Fucosidase / Q000008:administration & dosage*
chemical_list: D005644:alpha-L-Fucosidase