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The effects of intracisternal enzyme replacement versus sham treatment on central neuropathology in preclinical canine fucosidosis


Kondagari, GS and Fletcher, JL and Cruz, R and Williamson, P and Hopwood, JJ and Taylor, RM, The effects of intracisternal enzyme replacement versus sham treatment on central neuropathology in preclinical canine fucosidosis, Orphanet Journal of Rare Diseases, 10 pp. 1-12. ISSN 1750-1172 (2015) [Refereed Article]

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The Author(s) 2016. Open Access This article is licensed under a Creative CommonsAttribution 4.0 International (CC BY 4.0) License, ( which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.

DOI: doi:10.1186/s13023-015-0357-z


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.

Item Details

Item Type:Refereed Article
Keywords:lysosomal storage disease, fucosidosis, enzyme replacement therapy
Research Division:Biomedical and Clinical Sciences
Research Group:Neurosciences
Research Field:Neurology and neuromuscular diseases
Objective Division:Health
Objective Group:Clinical health
Objective Field:Treatment of human diseases and conditions
ID Code:147212
Year Published:2015
Web of Science® Times Cited:15
Deposited By:Menzies Institute for Medical Research
Deposited On:2021-10-19
Last Modified:2021-12-08
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