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Type: Journal article
Title: The effects of intracisternal enzyme replacement versus sham treatment on central neuropathology in preclinical canine fucosidosis
Author: Kondagari, G.
Fletcher, J.
Cruz, R.
Williamson, P.
Hopwood, J.
Taylor, R.
Citation: Orphanet Journal of Rare Diseases, 2015; 10(1):143-1-143-12
Publisher: BioMed Central
Issue Date: 2015
ISSN: 1750-1172
Statement of
Gauthami Sudhamayee Kondagari, Jessica Louise Fletcher, Rachel Cruz, Peter Williamson, John J. Hopwood and Rosanne Maree Taylor
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.
Keywords: Fucosidosis; Intracisternal enzyme replacement therapy; Neuroinflammatory markers; Canine model; Neurodegeneration; CNS
Description: Research
Rights: © 2016 Kondagari et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.
DOI: 10.1186/s13023-015-0357-z
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