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  • 1
    Keywords: CELLS ; GENE-TRANSFER ; MOUSE MODEL ; DEFICIENT MICE ; ENZYME REPLACEMENT THERAPY ; ALPHA-GALACTOSIDASE-A ; SUBSTRATE REDUCTION THERAPY ; TYPE-1 GAUCHER-DISEASE ; GLOBOTRIAOSYLCERAMIDE ; ISOGLOBOTRIHEXOSYLCERAMIDE
    Abstract: Fabry disease is a monogenic X-linked lysosomal storage disease caused by alpha-galactosidase A (alphaGalA) deficiency. Enzyme replacement therapy through administration of the missing alphaGalA is currently the only accepted therapeutic option. However, this treatment is connected to high costs, has ill-defined indication criteria and its efficacy is controversially discussed. Our aim was to explore the possibility of a novel targeted substrate reduction therapy for Fabry disease. Owing to the fact that alphaGalA-deficient humans and mice accumulate the same glycosphingolipids (i.e. globosides, galabiosylceramide and isoglobosides), alphaGalA-deficient mice were crossed with mice deficient in enzymes synthesizing these classes of glycosphingolipids (i.e. globotrihexosylceramide and isoglobotrihexosylceramide synthase, respectively). Functional heart and kidney tests were performed together with an extensive biochemical analysis of urine and serum in aged mice. Lysosomal storage was assessed by thin layer chromatography and electron microscopy. We showed that depletion of globosides was sufficient to fully abolish the storage of glycosphingolipids in heart, kidney and liver and was paralleled by a complete restoration of lysosomal morphology in these organs. In contrast, in dorsal root ganglia, a depletion of both globosides and isoglobosides was necessary to fully counteract the lysosomal storage. The deficiency in globosides and/or isoglobosides did not cause any adverse effects. We conclude that substrate reduction therapy through inhibition of the synthesis of globosides and isoglobosides represents a valuable therapeutic option for Fabry disease, all the more as globosides and isoglobosides seem to be dispensable.
    Type of Publication: Journal article published
    PubMed ID: 24992926
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  • 2
    Keywords: brain ; CELLS ; EXPRESSION ; IN-VITRO ; SURVIVAL ; AGENTS ; Germany ; MODEL ; THERAPY ; GENE ; PROTEIN ; PROTEINS ; gene therapy ; MICE ; TUMOR-NECROSIS-FACTOR ; IFN-GAMMA ; INFECTION ; ALPHA ; culture ; MOUSE ; VECTOR ; NECROSIS-FACTOR-ALPHA ; CELL-LINE ; LINE ; MINUTE VIRUS ; REPLICATION ; MOUSE MODEL ; INTERFERON ; sensitivity ; autonomous parvovirus ; mannose receptor ; CYTOTOXICITY ; FACTOR-ALPHA ; BRAIN-TUMORS ; CAPACITY ; GLIOMA ; parvovirus ; VIRIONS ; FUNCTIONAL-CHARACTERIZATION ; astrocytoma ; uptake ; CANDIDATE ; glial cells ; IMMUNE FUNCTION ; lipopolysaccharide ; MICROGLIAL CELLS
    Abstract: The sensitivity of brain tumour cells to wild-type or recombinant parvoviruses H1-PV and MVMp makes these agents promising candidates for gene therapy of astrocytoma. This application raises the question of whether parvoviruses exert deleterious or bystander effects on normal glial cells surrounding tumours. We addressed this question in the mouse model by using cell cultures derived from BALB/c, C57BL/6 and VM/Dk strains. Astrocytes and a large proportion of microglia cultures were competent for MVMp uptake. Infection was, however, abortive as replication-associated viral proteins synthesis took place in less than 10% of astrocytes and no progeny virions were produced. This restriction was even more pronounced for microglia in which no viral protein expression could be detected, save for a minute fraction of VM/Dk-derived cells. Infection with MVMp had no significant effect on glial cell survival and did not interfere with their immune potential. Indeed, neither the lipopolysaccharide (LPS)/interferon (IFN-gamma)-induced cytotoxicity of VM/Dk-derived microglia towards the mouse glioma (MT539MG) cell line, nor the glial cells capacity for tumour necrosis factor alpha production upon LPS stimulation or LPS/IFN-gamma stimulation were affected by infection with MVMp. Moreover, stimulation with LPS and/or IFN-gamma resulted in a decreased expression of the viral replicative and cytotoxic protein NS1. Together, our data indicate that, in the natural host, a majority of normal glial cells are not competent for MVMp replication and that the abortive infection taking place in a minor fraction of these cells fails to impede their survival and immunocompetence, giving credit to the consideration of autonomous parvoviruses for glioma therapy
    Type of Publication: Journal article published
    PubMed ID: 16699801
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  • 3
    Keywords: NETWORKS ; ALZHEIMERS-DISEASE ; TRANSGENIC MICE ; MOUSE MODEL ; ASTROCYTES ; VASCULAR NORMALIZATION ; metastasis formation ; CALCIUM WAVES ; IMAGING REVEALS ; 3 DIMENSIONS
    Abstract: A complex and reciprocal communication of cells with each other and with relevant parts of the tissue stroma governs many biological processes in both health and disease. However, in the past, the study of these anatomical and molecular interactions has suffered from a lack of appropriate experimental models. An imaging methodology aimed at changing this should allow intravital display and quantification in an intact non-traumatized organ, imaging over a wide range of time spans including extended periods (i.e., months), many repetitive measurements of the same cell or area to permit the study of the cause and consequence of biological processes, the display of various cell types and their reciprocal interaction with each other in three dimensions, the co-registration of relevant physiological parameters and reporters for selected molecular pathways and as high as possible resolution to visualize sub-cellular structures such as organelles. Remarkably, intravital multiphoton microscopy (in vivo MPLSM) through a chronic cranial window allows us to do all these things, making the brain the inner organ of choice for this technology. Here, we give an overview of the application of in vivo MPLSM to study the choreography of cellular, vascular and molecular interactions in the healthy brain and in neurological diseases. We focus on brain tumor formation, progression and response to therapies. This review further aims at demonstrating that we stand at the beginning of full exploitation of the opportunities provided by this technology and gives clues to future directions that appear most promising.
    Type of Publication: Journal article published
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