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

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          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.

          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.

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          Most cited references25

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          Effective gene therapy for an inherited CNS disease in a large animal model.

          Genetic diseases affecting the brain typically have widespread lesions that require global correction. Lysosomal storage diseases are good candidates for central nervous system gene therapy, because active enzyme from genetically corrected cells can be secreted and taken up by surrounding diseased cells, and only small amounts of enzyme (<5% of normal) are required to reverse storage lesions. Injection of gene transfer vectors into multiple sites in the mouse brain has been shown to mediate widespread reversal of storage lesions in several disease models. To study a brain closer in size to the human brain, we evaluated the extent of storage correction mediated by a limited number of adeno-associated virus vector injections in the cat model of human alpha-mannosidosis. The treated cats showed remarkable improvements in clinical neurological signs and in brain myelination assessed by quantitative magnetic resonance imaging. Postmortem examination showed that storage lesions were greatly reduced throughout the brain, even though gene transfer was limited to the areas surrounding the injection tracks. The data demonstrate that widespread improvement of neuropathology in a large mammalian brain can be achieved using multiple injection sites during one operation and suggest that this could be an effective treatment for the central nervous system component of human lysosomal enzyme deficiencies.
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            Intrathecal enzyme replacement therapy: successful treatment of brain disease via the cerebrospinal fluid.

            Treatment of brain disease with recombinant proteins is difficult due to the blood-brain barrier. As an alternative to direct injections into the brain, we studied whether application of high concentrations of therapeutic enzymes via intrathecal (IT) injections could successfully drive uptake across the ependyma to treat brain disease. We studied IT enzyme replacement therapy with recombinant human iduronidase (rhIDU) in canine mucopolysaccharidosis I (MPS I, Hurler syndrome), a lysosomal storage disorder with brain and meningeal involvement. Monthly or quarterly IT treatment regimens with rhIDU achieved supranormal iduronidase enzyme levels in the brain, spinal cord, and spinal meninges. All regimens normalized total brain glycosaminoglycan (GAG) storage and reduced spinal meningeal GAG storage by 58-70%. The improvement in GAG storage levels persisted three months after the final IT dose. The successful use of enzyme therapy via the CSF represents a potentially useful approach for lysosomal storage disorders.
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              Inflammation, apoptosis, and Alzheimer's disease.

              The pathophysiology of Alzheimer's disease (AD) involves the deposition of amyloid in the brain and the extensive loss of neurons. The mechanisms subserving neuronal death in the disease remain unclear, although it has been postulated that this is due to apoptosis. There is compelling evidence that inflammatory processes play a role in disease progression and pathology. Amyloid plaque deposition is accompanied by the association of microglia with the senile plaque, and this interaction stimulates these cells to undergo phenotypic activation and the subsequent elaboration of proinflammatory and neurotoxic products. This review focuses on the mechanisms by which neurons are lost in AD and the role microglial proinflammatory products play in neuronal death.
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                Author and article information

                Contributors
                +61 2 9351 6936 , rosanne.taylor@sydney.edu.au
                Journal
                Orphanet J Rare Dis
                Orphanet J Rare Dis
                Orphanet Journal of Rare Diseases
                BioMed Central (London )
                1750-1172
                4 November 2015
                4 November 2015
                2015
                : 10
                : 143
                Affiliations
                [ ]Faculty of Veterinary Science, University of Sydney, Camperdown, NSW 2006 Australia
                [ ]Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, Adelaide, SA 5000 Australia
                Article
                357
                10.1186/s13023-015-0357-z
                4632352
                26537923
                14b04c76-e038-4043-888b-909fe1f81b60
                © 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.

                History
                : 18 July 2015
                : 16 October 2015
                Categories
                Research
                Custom metadata
                © The Author(s) 2015

                Infectious disease & Microbiology
                fucosidosis,intracisternal enzyme replacement therapy,neuroinflammatory markers,canine model,neurodegeneration,cns

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