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The effects of intracisternal enzyme replacement versus sham treatment on central neuropathology in preclinical canine fucosidosis
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 neuropatho...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4632352/ https://www.ncbi.nlm.nih.gov/pubmed/26537923 http://dx.doi.org/10.1186/s13023-015-0357-z |
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author | Kondagari, Gauthami Sudhamayee Fletcher, Jessica Louise Cruz, Rachel Williamson, Peter Hopwood, John J. Taylor, Rosanne Maree |
author_facet | Kondagari, Gauthami Sudhamayee Fletcher, Jessica Louise Cruz, Rachel Williamson, Peter Hopwood, John J. Taylor, Rosanne Maree |
author_sort | Kondagari, Gauthami Sudhamayee |
collection | PubMed |
description | 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13023-015-0357-z) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4632352 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-46323522015-11-05 The effects of intracisternal enzyme replacement versus sham treatment on central neuropathology in preclinical canine fucosidosis Kondagari, Gauthami Sudhamayee Fletcher, Jessica Louise Cruz, Rachel Williamson, Peter Hopwood, John J. Taylor, Rosanne Maree Orphanet J Rare Dis Research 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13023-015-0357-z) contains supplementary material, which is available to authorized users. BioMed Central 2015-11-04 /pmc/articles/PMC4632352/ /pubmed/26537923 http://dx.doi.org/10.1186/s13023-015-0357-z Text en © Kondagari et al. 2015 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), 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 (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Kondagari, Gauthami Sudhamayee Fletcher, Jessica Louise Cruz, Rachel Williamson, Peter Hopwood, John J. Taylor, Rosanne Maree The effects of intracisternal enzyme replacement versus sham treatment on central neuropathology in preclinical canine fucosidosis |
title | The effects of intracisternal enzyme replacement versus sham treatment on central neuropathology in preclinical canine fucosidosis |
title_full | The effects of intracisternal enzyme replacement versus sham treatment on central neuropathology in preclinical canine fucosidosis |
title_fullStr | The effects of intracisternal enzyme replacement versus sham treatment on central neuropathology in preclinical canine fucosidosis |
title_full_unstemmed | The effects of intracisternal enzyme replacement versus sham treatment on central neuropathology in preclinical canine fucosidosis |
title_short | The effects of intracisternal enzyme replacement versus sham treatment on central neuropathology in preclinical canine fucosidosis |
title_sort | effects of intracisternal enzyme replacement versus sham treatment on central neuropathology in preclinical canine fucosidosis |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4632352/ https://www.ncbi.nlm.nih.gov/pubmed/26537923 http://dx.doi.org/10.1186/s13023-015-0357-z |
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