Dissertations / Theses on the topic 'Mucopolysaccharidosi'
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Pereira, Cátia Daniela Isaías. "Lymphocyte populations in Mucopolysaccharidosis patients." Master's thesis, Universidade de Aveiro, 2015. http://hdl.handle.net/10773/15580.
Full textAs doenças de sobrecarga lisossomal (DSLs) constituem um grupo de distúrbios metabólicos raros maioritariamente causados por mutações em hidrolases lisossomais, que conduzem à acumulação anormal de diferentes substratos macromoleculares no interior do lisossoma. Este trabalho é focado nas mucopolissacaridoses (MPSs), um grupo de DSLs resultantes da atividade deficiente de enzimas envolvidas no catabolismo dos glicosaminoglicanos. A MPS II é caraterizada pela perda de atividade da enzima iduronato-2-sulfatase, levando ao armazenamento intralisossomal de sulfato de dermatano e sulfato de heparano. A MPS VI é definida pela acumulação de sulfato de dermatano dentro do lisossoma, devido a uma deficiência na atividade enzimática de arilsulfatase B. O lisossoma é um compartimento celular importante para o funcionamento normal do sistema imunitário. Em diversos modelos de DSLs, foram anteriormente descritas alterações nas células do sistema imunitário. Os principais objetivos do presente trabalho eram: (i) estudar as várias populações leucocitárias – incluindo células T e seus subconjuntos, células natural killer (NK), células B e suas subpopulações, e monócitos – no sangue periférico de doentes com MPS II e MPS VI; (ii) produzir linhas de células B transformadas pelo vírus Epstein–Barr (EBV) destes pacientes, assim como avaliar a eficácia na sua produção e determinar o seu fenótipo. A caraterização do sistema imunitário nas doenças MPS II e MPS VI revelou um decréscimo significativo na frequência de células NK e monócitos em doentes com MPS VI, mas não em doentes com MPS II, em comparação com indivíduos controle. Em contraste, não foram identificadas alterações na percentagem de células T, células natural killer T invariantes (iNKT) e células B nos grupos de doentes com MPS II e MPS VI, comparando com o grupo controlo. A análise detalhada do estado de memória de células T auxiliares e células T citotóxicas revelou desequilíbrios nos fenótipos naïve e de memória em ambos os compartimentos de células T em doentes com MPS VI, mas não em doentes com MPS II, em comparação com indivíduos controle. As linhas de células B transformadas pelo EBV foram produzidas com sucesso nos dois grupos de doentes com MPS, mas a eficácia na sua produção foi superior no caso dos doentes com MPS VI, comparando com os indivíduos controle e doentes com MPS II. O fenótipo predominante das linhas de células B transformadas pelo EBV era similar entre ambos os grupos de doentes com MPS e o grupo controlo, o qual foi avaliado como sendo correspondente à subpopulação de células B de memória duplamente negativas. Em conclusão, este trabalho permitiu caraterizar melhor o sistema imunitário nestas duas doenças raras.
Lysosomal storage diseases (LSDs) constitute a group of rare metabolic disorders mostly caused by mutations in lysosomal hydrolases, which conduce to abnormal accumulation of different macromolecular substrates inside the lysosome. This work is focused on the mucopolysaccharidoses (MPSs), a group of LSDs arising from the deficient activity of enzymes involved in the catabolism of glycosaminoglycans. The MPS II is characterized by loss of activity of the enzyme iduronate-2-sulfatase, leading to the intralysosomal storage of dermatan sulfate and heparan sulfate. The MPS VI is defined by the accumulation of dermatan sulfate within the lysosome, owing to a deficiency in the enzymatic activity of arylsulfatase B. The lysosome is an important cellular compartment for the normal functioning of the immune system. In several models of LSDs, alterations in the immune system cells were previously described. The main aims of the present work were: (i) to study the various leukocyte populations – including T cells and their subsets, natural killer (NK) cells, B cells and their subpopulations, and monocytes – in the peripheral blood of MPS II and MPS VI patients; (ii) to produce Epstein–Barr virus (EBV)- -transformed B cell lines from these patients, as well as to evaluate the efficacy in their generation and determine their phenotype. The characterization of the immune system in MPS II and MPS VI diseases revealed a significant decrease in the frequency of NK cells and monocytes in MPS VI patients, but not in MPS II patients, in comparison with control subjects. In contrast, no alterations were identified in the percentage of T cells, invariant natural killer T (iNKT) cells, and B cells in the groups of MPS II and MPS VI patients comparing with the control group. The detailed analysis of the memory state of helper T cells and cytotoxic T cells revealed imbalances in the naïve and memory phenotypes in both T cell compartments in MPS VI patients, but not in MPS II patients, as compared with control subjects. The EBV-transformed B cell lines were successfully produced in the two MPS patient groups, but the efficacy in their generation was higher in the case of MPS VI patients when comparing with control subjects and MPS II patients. The predominant phenotype of EBV-transformed B cell lines was similar between both groups of MPS patients and the control group, which was assessed as corresponding to the double-negative memory B cell subpopulation. In conclusion, this work allowed to better characterize the immune system in these two rare diseases.
Kesenheimer, Johannes. "Diagnostik der Mucopolysaccharidose IV – Morquio Syndrom." Diss., lmu, 2012. http://nbn-resolving.de/urn:nbn:de:bvb:19-146349.
Full textLutzko, Carolyn Mary. "Gene therapy for canine mucopolysaccharidosis type I." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape7/PQDD_0006/NQ41221.pdf.
Full textLitjens, Tom. "The molecular genetics of mucopolysaccharidosis type VI /." Title page, contents and abstract only, 1994. http://web4.library.adelaide.edu.au/theses/09PH/09phl776.pdf.
Full textScott, Hamish Steele. "The molecular genetics of mucopolysaccharidosis type I /." Title page, contents and summary only, 1992. http://web4.library.adelaide.edu.au/theses/09PH/09phs426.pdf.
Full textLopes, Nuno Duarte Ribeiro. "iNKT cells in mucopolysaccharidosis type II patients." Master's thesis, Universidade de Aveiro, 2013. http://hdl.handle.net/10773/11621.
Full textA Mucopolissacaridose tipo II (MPS II) é uma Doença de Sobrecarga Lisossomal (LSD) pertencente às mucopolissacaridoses. É caracterizada pela acumulação de sulfato de heparan e dermatan devido à deficiência na enzima lisossomal Iduronato 2-Sulfatase. O lisossoma é um compartimento importante para a atividade dos linfócitos iNKT (iNKT). Os linfócitos iNKT são linfócitos T restritos a lípidos envolvidos na infeção, autoimunidade e vigilância tumoral. Estudos anteriores em modelos de murganhos de LSDs demonstraram uma redução do número de linfócitos iNKT assim como alterações nas subpopulações de linfócitos iNKT. Apesar destes resultados, investigação similar em doentes humanos foi ainda pouco abordada. Aqui, analisamos pela primeira vez os linfócitos iNKT de doentes com MPS II. Os dados foram recolhidos através da análise por citometria de fluxo de Células Mononucleares do Sangue Periférico de doentes com MPS II. Os doentes com MPS II não apresentavam diferenças nos linfócitos iNKT totais nem nas subpopulações de linfócitos iNKT. Fenotipicamente, não foram encontradas, nestas células, alterações na expressão de marcadores de ativação e de linfócitos NK. Uma vez que a ativação de linfócitos iNKT requer o funcionamento do lisossoma das células apresentadoras de antigénios, analisámos as suas frequências e fenótipos. Foram encontradas reduções significativas nos monócitos de doentes e não foram encontradas alterações nas restantes células. Não foram encontradas alterações fenotípicas nas células apresentadoras de antigénios. A comparação dos resultados apresentados nesta tese com os resultados previamente obtidos no nosso laboratório para outras LSD sugere que o desenvolvimento dos linfócitos iNKT é influenciado pela natureza das moléculas acumuladas. Descrevemos ainda pela primeira vez alterações na percentagem de monócitos no sangue de doentes com MPS II.
Mucopolysaccharidosis type II (MPS II) is a Lysosomal Storage Disorder (LSD) belonging to the group of mucopolysaccharidoses. It is characterised by the accumulation of heparan and dermatan sulfate due to deficiency of the lysosomal enzyme Iduronate 2-Sulfatase. The lysosome is an important compartment for the activity of invariant Natural Killer T cells (iNKT). iNKT cells are lipid-specific T cells that were shown to be important in infection, autoimmunity and tumour surveillance. Previous studies in mouse models of LSDs have shown a decrease in iNKT cell numbers and alterations in iNKT cell subsets. In spite of these findings, similar research in human patients has been poorly addressed. Herein, we analysed for the first time iNKT cells from Mucopolysaccharidosis type II patients. Data was acquired through flow cytometry analysis of Peripheral Blood Mononuclear Cells from MPS II patients. MPS II patients did not present differences in total iNKT cells neither in iNKT cell subsets. Phenotypically, no differences have been found in the expression of activation and NK cells markers. Since iNKT cell activation requires a functioning lysosome of antigen presenting cells, we analysed their frequency and phenotype. We have found a significant reduction in monocytes from patients and no differences in the other cells. Furthermore, no phenotypical alterations have been found in antigen presenting cells. The comparison of the results presented in this thesis with the results previously obtained by our laboratory in other LSD suggests that iNKT cell development is influenced by the nature of the accumulated molecules. We also described for the first time alterations in the percentage of monocytes in the peripheral blood of MPS II patients.
PARIS, ERIC. "Circonstances inhabituelles du diagnostic des mucopolysaccharidoses." Rennes 1, 1993. http://www.theses.fr/1993REN1M058.
Full textMaia, Maria da Luz Galante. "Lipid specific T cells in Mucopolysaccharidosis VI patients." Master's thesis, Universidade de Aveiro, 2012. http://hdl.handle.net/10773/10388.
Full textDoenças de sobrecarga lisossomal (DSL) são um grupo de doenças metabólicas hereditárias causadas pela acumulação de moléculas não degradadas nos lisossomas, devido sobretudo a defeitos em enzimas lisossomais. Mucopolissacaridoses são DSL caracterizadas pela acumulação de glicosaminoglicanos anteriormente designados mucopolissacarídeos. O foco deste trabalho é a Mucopolissacaridose tipo VI (MPS VI), que resulta da defeciência de uma hidrolase lisossomal (Arylsulfatase B) responsável pela degradação do sulfato de dermatan, o que leva á acumulação desta macromolécula nos doentes. O lisossoma é um organelo importante na apresentação de antigénios lipídicos ás células T. A apresentação de antigénios lipídicos é mediada por moléculas CD1 existentes nas células apresentadoras de antigénios. A ligação do antigénio lipídico ás moléculas CD1 das células apresentadoras leva á activação das células T restritas a CD1 (NKT). Existem cinco isoformas de moléculas CD1 (a, b, c, d, e), mas apenas quatro são capazes de apresentar antigénios (a, b, c, d). Um dos locais na célula onde a associação das moléculas CD1 com os antigénios lipídicos ocorre é o lisossoma, portanto a apresentação de antigénios lipídicos pode estar afectada em doentes com DSL. Células NKT são um grupo heterogéneo de células T que partilham propriedades das células T e das células natural killer . Em humanos existem três subpopulações de células iNKT dependendo da expressão de CD4 e CD8: CD4+ (apenas expressam CD4), CD8+ (apenas expressam CD8) e duplas negativas (DN) que não expressam nenhumas das duas moléculas. Em estudos prévios foi observado em modelos animais de várias DSL uma diminuição na percentagem de células iNKT. Em doentes de Fabry e Gaucher não foram encontradas alteraçoes. O objectivo deste trabalho é estudar os linfócitos incluindo as células iNKT, as células dendríticas (como células apresentadoras de antigénios) e apresentação de antigénios lipídicos em doentes com MPS VI. Não foram encontradas alterações na percentagem de células iNKT assim como nas suas subpopulações entre doentes com MPS VI e indivíduos controlos. Curiosamente encontramos um aumento na percentagem de linfócitos B em doentes com MPS VI quando comparados com indivíduos controlo. Para determinar o fenótipo das células dendríticas três doentes foram analisados, encontramos para alguns destes doentes uma diminuição na expressão das moléculas CD1a, CD11c e HLA-DR (MHC-class II), mas para tirar mas conclusões mais doentes precisam ser analisados. Três doentes com MPS VI foram analisados para testar a capacidade das suas células dendríticas apresentarem antigénios lipídicos pela molécula CD1b. Não foram encontradas alterações na capacidade destes doentes apresentarem o antigénio lipídico GM1 pela molécula CD1b. Pela primeira vez foram realizados ensaios de apresentação de antigénios lipídicos em doentes com MPS.
Lysosomal storage diseases (LSD) are a group of hereditary metabolic disorders caused by accumulation of undegraded molecules in the lysosome, mainly due to the impairment of the function of lysosomal enzymes. Mucopolysaccharidoses are LSDs characterized by the accumulation of glycosaminoglycans previously designated Mucopolysaccharides. The focus of this work is the Mucopolysaccharidosis type VI (MPS VI), which is a disorder caused by a deficiency in a lysosomal hydrolase (Arylsulfatase B) responsible for the dermatan sulfate degradation, that leads to an accumulation of this macromolecule in the patients. Lysosome is an important organelle in the presentation of lipid antigen to T cells. Lipid antigen presentation is mediated by CD1 molecules existent in the antigen presenting cells. The binding of lipid antigens and the presenting cells containing CD1 molecules lead to activation of T cells that respond to those molecules. There are five isoforms of CD1 molecules (a, b, c, d, e), but only four are antigen presenting (a, b, c, d). One of the cell locations where the association of the CD1 molecules and lipid antigens occurs is the lysosome, so that means that antigen presentation could be affected in LSDs patients. NKT cells are a heterogeneous group of T cells that share properties with T cells and natural killer cells. In humans there are three subpopulations depending on the expression of CD4 and CD8 molecules: CD4+ (only express CD4), CD8+ (only express CD8) and double negative (DN) that do not express any of them. In previous studies a decrease in the percentage of iNKT cells were observed in mouse models of several LSDs. However in patients with Fabry and Gaucher diseases no alterations were found. The aim of this work is to study the lymphocytes including the iNKT cells, the dendritic cells (as antigen presenting cells) and the lipid antigen presentation in MPS VI patients. We found no alterations in the percentage of the iNKT cells and in their subsets between MPS VI patients and control subjects. Interestingly we found an increase in the percentage of the B lymphocyte population in MPS VI patients when compared with control subjects. For dendritic cells phenotype three patients were analyzed, we found for some of them a decrease of the expression of CD1a, CD11c and HLA-DR (MHC-class II) however, more patients need to be study before conclusions can be drawn. In lipid antigen presenting assays, three patients were tested for the capacity of their dendritic cells to present lipid antigens by CD1b molecule. We found no alterations in patients’ capacity to present the lipid antigen GM1 by CD1b molecule. Studies regarding the lipid antigen presentation were for the first time performed in MPS.
LLADO, SANTAEULARIA MANEL. "THERAPEUTIC GENOME EDITING IN RETINA AND LIVER." Doctoral thesis, Università degli Studi di Milano, 2020. http://hdl.handle.net/2434/696628.
Full textChodan, Desmaris Nathalie. "Thérapie génique des atteintes neurologiques dans les mucopolysaccharidoses." Paris 7, 2004. http://www.theses.fr/2004PA077039.
Full textRoy, Elise. "Cell disorders in lysosomal storage diseases." Phd thesis, Université René Descartes - Paris V, 2012. http://tel.archives-ouvertes.fr/tel-00683248.
Full textHeppner, Jonathan Michael. "Early disruption of the extracellular matrix in murine mucopolysaccharidosis I." Thesis, University of British Columbia, 2015. http://hdl.handle.net/2429/54160.
Full textMedicine, Faculty of
Medical Genetics, Department of
Graduate
O'Leary, H. A. ngharad E. S. G. "Heparan sulphate inhibits haematopoietic stem cell homing in mucopolysaccharidosis I." Thesis, University of Manchester, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.528510.
Full textGliddon, Briony Lee. "Enzyme replacement therapy in a murine model of mucopolysaccharidosis type IIIA /." Title page, contents and abstract only, 2002. http://web4.library.adelaide.edu.au/theses/09PH/09phg5595.pdf.
Full textCrawley, Allison Catherine. "Enzyme replacement therapy in a feline model of mucopolysaccharidosis type VI /." Title page, contents and abstract only, 1998. http://web4.library.adelaide.edu.au/theses/09PH/09phc9107.pdf.
Full textSAYEGH, SAMI. "La readaptation de la maladie de morquio : a propos de 16 observations, dont une fratrie de cinq personnes, du centre des massues." Lyon 1, 1992. http://www.theses.fr/1992LYO1M051.
Full textDE, JONCKHEERE CHANTAL, and YVES GIRKA. "Maladie de hunter (mucopolysaccharidose de type ii) : a propos de 3 observations." Lille 2, 1990. http://www.theses.fr/1990LIL2M212.
Full textLAMBATTEN, DRISS. "La maladie de hunter." Lille 2, 1988. http://www.theses.fr/1988LIL2M236.
Full textBruyere, Julie. "Cascades physiopathologiques dans la maladie de Sanfilippo B." Thesis, Paris 5, 2012. http://www.theses.fr/2012PA05T020/document.
Full textMucopolysaccharidosis type IIIB (Sanfilippo B disease) is a lysosomal storage disease characterized by severe neurological manifestations in children. This rare monogenic disease is caused by a-Nacetylglucosaminidase (NAGLU) deficiency, a lysosomal hydrolase necessary for heparan sulfate (HS) degradation. This deficiency leads to the accumulation of HS saccharides. Mechanisms mediating HS saccharides deleterious effects on brain cells are not well understood. This research provides evidences that neural cell sensing of environment is altered in MPSIIIB cells. Integrins and focal adhesion components are over-recruited and over-activated in deficient mouse astrocytes. Consistently, integrin-dependant cell behavior such as cell polarization and directed migration were defective in affected astrocytes and neural stem cells. HS saccharide clearance, by NAGLU gene transfer, rescues a normal phenotype suggesting that HS saccharides induce focal adhesion formation. Addition of purified HS saccharides on normal astrocytes confirms that extracellular HS saccharides can activate the recruitment of focal adhesion components and provides an in vitro assay to decipher the saccharide code of HS. Otherwise, investigations performed on HeLa cell model, in which NAGLU expression was inhibited by shRNA, showed that accumulation of intracellular storage vesicles, a hallmark of the disease, is due over expression of a cis-Golgi protein. This affects the Golgi morphology and microtubule nucleation and stability. It seems that alterations of environment cell sensing and downstream signaling also modify the dynamic and the structure of cells. We assume that mechanisms deciphered in cell cultures are related to MPSIIIB neuropathology. By affecting cell perception of environmental cues, cell polarity, cell migration and neurite outgrowth, HS saccharides, which accumulate in brain tissues defective for a HS degradation enzyme, likely affect various processes important for accurate cortical maturation
Zarrinkalam, Krystyna. "Characterisation of osteoblast function in a feline model of mucopolysaccharidosis type VI." Title page, contents and introduction only, 2001. http://web4.library.adelaide.edu.au/theses/09PH/09phz38.pdf.
Full textLangford-Smith, Alexander William Walker. "Lentiviral vector mediated haematopoietic stem cell gene therapy for mucopolysaccharidosis type IIIA." Thesis, University of Manchester, 2012. https://www.research.manchester.ac.uk/portal/en/theses/lentiviral-vector-mediated-haematopoietic-stem-cell-gene-therapy-for-mucopolysaccharidosis-type-iiia(89f8e108-58f3-42bb-8b80-0e0a1fe45fd7).html.
Full textMONTAGNA, ANNA. "Induced pluripotent stem cells (IPSCS) for modelling mucopolysaccharidosis type I (Hurler syndrome)." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2016. http://hdl.handle.net/10281/113869.
Full textBitencourt, Fernanda Hendges de. "Aspectos farmacoeconômicos associados à terapia de reposição enzimática para mucopolissacaridoses tipo I, II e VI : um estudo com ênfase em intervenções médicas." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2013. http://hdl.handle.net/10183/71291.
Full textIntroduction: The mucopolysaccharidoses type I (MPS I), II (MPS II) and VI (MPS VI) are lysosomal disorders (LSD) for which enzyme replacement therapy (ERT) with laronidase, idursulfase and galsulfase, respectively, are available. Principal objective: To analyze the annual frequency of medical interventions (number of medical appointments, hospital admissions, surgical procedures, exams performed, medications prescribed, ancillary therapies and the use of medical devices) in a sample of Brazilian patients with MPS I, II and VI, and thus, contribute to the understanding of some pharmacoeconomic aspects related to these diseases. Methodology: Retrospective, exploratory, hospital-based study, based on medical records review, with convenience sampling, which was conducted in two steps (steps 1 and 2). A specific data collection instrument for both steps was designed by the study team, which is multidisciplinary. The chosen outcomes were: annual frequencies of medical interventions (medical appointments, exams, surgical procedures, hospital admissions, medications used and ancillary therapies). Step 1 was a pre-experimental study conducted at the Medical Genetics Service of Hospital de Clínicas de Porto Alegre (SGM-HCPA), and compared the variables of interest between the pre and post-ERT periods for the same group of patients. The patient inclusion criteria were: a biochemical diagnosis of MPS I and regular follow-up at SGM-HCPA since diagnosis; ERT for at least 1 year; no enrollment in any clinical trials involving ERT, and no history of hematopoietic stem cell transplantation. Step 2 was a cross-sectional and multicentric estudy (Centers included: SGM-HCPA), the Department of Medical Genetics of Universidade Estadual de Campinas - UNICAMP, Pontifícia Universidade Católica de Campinas - PUC-Campinas, and the Department of Pediatrics at Universidade Estadual do Rio de Janeiro – UERJ, which compared the variables of interest between different groups of patients (those receiving and those not receiving ERT). For this step only data from 2010 were considered. The inclusion patient criteria were: a biochemical diagnosis of MPS I, II or VI; no enrollment in any clinical trials involving ERT, and no history of hematopoietic stem cell transplantation, to be on ERT for at least 12 months before the start of data collection or to undergo regular follow-up for at least 12 months before the start of data collection. Results: Step 1 – Nine MPS I patients (severe=3; attenuated phenotype=6) were included in the study with median age at diagnosis was 4.4 years. Only the number/year/patient of surgeries was found to be dependent on length of disease (p=0.0004) and on severity of phenotype (p=0.014). Regarding pre- and post-ERT comparisons, the variables for which a significant difference was detected (mean number/year/patient) were exams (pre-ERT, 10.2±2.7; post-ERT, 22.5±2.1; p=0.005) and hospital admissions (pre-ERT, 0.05±0.04; post-ERT, 0.30±0.11; p=0.013). For the other variables, no association was found. Step 2: Thirty-four patients with MPS I, II and VI were included (I=12, II=17, VI=5). From them, 27 on ERT (“ERT group”) and 7 receiving supportive care only (“non-ERT group”). There were no significant correlation between length of disease and any of the variables of interest. There were significant between-group differences in the median number of hospital admissions and surgical procedures, both of which were higher in the non-ERT group [1(0-2) vs. 0 (0-1), p=0,015; e 0 (0-2) vs. 0 (0-0), p=0,040, respectively]. There were no significant between-group differences when only children and adolescents (<18 years) were taken into account. Patients with cognitive involvement used more medications than the others (p=0.024). A correlation was detected between time on ERT and the hospital admissions variable (r= -0.504; p=0.007). Discussion/conclusions: This was one of the first studies to evaluate aspects related to pharmacoeconomics of ERT for MPS. According to the results of step 2, and not acknowledging the costs associated with recombinant enzyme infusions, patients with MPS who undergo ERT generate less cost to SUS than patients on symptomatic treatment. On the other hand, according to the results of step 1, ERT seems not to stop the disease progress, at least in respect to MPS I, and thus, for each year of a patient life occurred an increase in cost associated with treatment. Additional studies with larger sample size are needed to confirm our findings.
Nelson, John. "The mucopolysaccharidoses in Northern Ireland : a clinical, genetic and biochemical study." Thesis, Queen's University Belfast, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.357486.
Full textBodet, Pierre-Edouard. "Recherche de biomarqueurs glucidiques de mucopolysaccharidoses et étude de la physiopathologie." Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLE001/document.
Full textThe identification of biomarkers remains one of the main challenges for analytical sciences and a major stake for clinical research. Glycosaminoglycans (GAGs) have been identified as potential biomarkers of mucopolysaccharidoses (MPS) belonging to rare genetic diseases with often a deadly issue. These pathologies are due to a deficiency in one of the enzymes responsible for GAGs catabolism. This enzymatic defect results in the accumulation of partially catabolized GAGs in organism and leads to neurodegeneration for the most severe forms of the disease. GAGs are complex polyanionic polysaccharides involved in numerous physiological processes in mammals. Their study remains a challenging task because of their high structural heterogeneity and their low biodisponibility, besides the lack of dedicated analytical tools. Our aim was to detect and quantify these compounds in biologic fluids such as urine and cerebrospinal fluid, and to elucidate their structures by mass spectrometry. This study focused on heparan sulfate (HS) oligosaccharides, as potential biomarkers of MPS featured by neurological manifestations (MPS I, IIIB and IIIC), and possibly responsible of lesions in the central nervous system. An experimental strategy allowing the extraction of HS oligosaccharides from biological fluids was implemented, thereby the structures of urinary heparan sulfate oligosaccharides were deciphered, leading to possible biomarkers candidates of MPS IIIB and IIIC. These compounds could be useful for diagnostic and patient follow-up that are currently lacking for the monitoring of therapeutic assays. In vitro exposition of different cerebral cell types to HS oligosaccharides was carried out to establish the relation between the structure of oligosaccharides and neuropathological effects. These studies highlighted several cellular processes that could be involved in neurodegeneration and constitute new therapeutic targets
Lehtonen, Annukka. "Social functioning and behaviour in mucopolysaccharidosis type I and other developmental genetic disorders." Thesis, University of Manchester, 2017. https://www.research.manchester.ac.uk/portal/en/theses/social-functioning-and-behaviour-in-mucopolysaccharidosis-type-i-and-other-developmental-genetic-disorders(e048920a-f3b8-4a9d-aebf-349ee3da411f).html.
Full textHocquemiller, Michaël. "Anomalies intrinsèques des neurones corticaux dans le modèle murin de la mucopolysaccharidose IIIB." Paris 5, 2009. http://www.theses.fr/2009PA05T007.
Full textSanfilippo B disease or mucopolysaccharidosis IIIB (MPSIIIB) is a lysosomal storage disease characterized by accumulation of partialially degraded oligosaccharides derived from heparan sulfate due to the defect of the N-acetyl-a-D-glucosaminidase enzyme (NaGlu). Mechanisms representatives for the alteration of the nervous system, which predominates in this syndrom, are poorly known. This study which was conducted on cortical neurons of the mouse model of MPSIIIB showed : I) accumulation of immobile and swollen lysosomes linked to the impairment of the early secretory pathway II) a strongly lost of synaptophysin expression linked to its enhanced degradation by the proteasome, III) neurites outgrowth abnormalities in culture linked to GAP43 overexpression. These intrinsic abnormalities could reflect the alteration of the neural plasticity responsible for defects in cognitive development of affected childrens and define new markers for this disease
Bellesso, Stefania. "Deregulated FGF signaling substantially contributes to early osteogenic defects in Mucopolysaccharidosis type II." Doctoral thesis, Università degli studi di Padova, 2017. http://hdl.handle.net/11577/3424774.
Full textLa via di segnale FGF è una importante pathway coinvolta in diverse fasi dell’osteogenesi e mutazioni che colpiscono componenti di questa via sono associate a diverse malattie umane come le craniosinostosi e le condrodisplasie. La regolazione della via di segnale FGF avviene a diversi livelli, sia con meccanismi intracellulari che tramite l’interazione con i glicosaminoglicani (GAGs) presenti nella matrice extracellulare, i quali possiedono un ruolo critico nell’interazione fra ligando e recettore. In questo lavoro viene dimostrato che alterazioni nella funzionalità dell’enzima iduronato 2-sulfatasi (IDS), coinvolto nel catabolismo dei GAGs, sono responsabili dell’alterazione della via di segnale FGF. La mancata o deficitaria attività dell’enzima IDS è causa dell’insorgenza di una rara patologia da accumulo lisosomiale chiamata Mucopolisaccaridosi di tipo II, nella quale uno degli aspetti più disabilitanti è rappresentato da manifestazioni patologiche dell’apparato scheletrico. La terapia comunemente impiegata è la somministrazione dell’enzima ricombinante (Enzyme Replacement Therapy, ERT) che, pur determinando un miglioramento di una parte della sintomatologia, non risulta efficace, o comunque risulta scarsamente efficace, in distretti importanti come cuore e sistema scheletrico. Per lo studio della patogenesi molecolare della MPSII e la comprensione dei meccanismi patogenetici che inducono alterazioni precoci nello sviluppo osseo, è stato utilizzato lo zebrafish come modello. Zebrafish risulta infatti un buon modello perché semplice da manipolare geneticamente; inoltre, in esso, il controllo delle principali vie di segnale che regolano il suo sviluppo osseo è altamente conservato. Sono stati generati sia modelli transienti con l’utilizzo della tecnica oligo morfolino, sia un mutante stabile applicando il metodo Crispr/Cas9. Utilizzando diversi approcci sperimentali, comprese tecniche di ibridazione in situ e transgenesi, è stato dimostrato che la mancata funzionalità dell’IDS determina alterazioni nell’espressione di marcatori chiave della via di segnale FGF e della differenziazione ossea a stadi molto precoci, prima di un evidente accumulo di glicosaminoglicani nei tessuti. L’alterazione di questa pathway è stata osservata anche in campioni di ossa craniche e appendicolari di topi IDS-KO e in fibroblasti di pazienti Hunter. I risultati di questo studio suggeriscono dunque che nella MPSII disfunzioni dell’enzima IDS inducano, in fasi precoci, alterazioni nella regolazione della via di segnale FGF, che a loro volta possono essere responsabili dell’alterata espressione di geni coinvolti nello sviluppo osseo, prima che si verifichi l’accumulo dei GAGs nei lisosomi.
DE, PONTI GIADA. "Exploring early therapeutic approaches in a Mucopolysaccharidosis type I (MPS I) mouse model." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2022. http://hdl.handle.net/10281/382061.
Full textThe present PhD project has taken into account critical issues around Mucopolysaccharidosis type I (MPSI) and limitations of current therapies to further improve them, by generally focusing on neonatal therapeutic approaches, both in terms of combined HSCT and ERT and of gene therapy, and on trying to reduce the overall toxicities associated with pre-conditioning settings. Overall, the most important open issues regarding this rare life-threatening disorder are the need for a precocious and rapid intervention, the lack of complete disease correction after current therapeutic approaches and side effects due to pre-conditioning regiment. My PhD project partially focused on testing a combined approach of the current standard-of-cares for treating MPSI. HSCT and ERT combination efficacy was tested in a mouse model of MPSI as neonatal intervention, for evaluating additional benefits of continuous enzyme therapy after transplant of donor’s cells. We compared three treatment options starting from MPSI pups’ birth, considering IDUA deficient activity, GAGs storage and vacuoles in visceral organs, the immune response against the recombinant IDUA and skeletal and CNS ameliorations. Therefore, performing a combined approach of HSCT and ERT in the neonatal period could help improving some hard-to-treat MPSI manifestations. The second part of this PhD project was carried out in collaboration with TIGET-SR and Prof. Alessandro Aiuti. It was focused on testing a neonatal gene therapy approach in a mouse model of MPSI, considering the importance of an early phenotype correction. In particular, we evaluated if this early treatment could be applied in MPSI neonates and could be a successful strategy for overcoming the main clinical issues that still remain after current canonical HSCT treatment. We monitored peripheral blood of treated mice for 8 months in terms of enzymatic activity and VCN, and we evaluated the effect of GT performed in MPSI pups at endpoint, considering IDUA deficient activity, vector copies/genome, GAGs storage and vacuoles in visceral organs, the immune response against the recombinant IDUA and skeletal and CNS ameliorations. The last part of this PhD project was centered on trying to reduce the high morbidity and mortality due to the severe conditioning regimen in the context of neonatal MPSI therapies, as a side project. The main objective was to translate the application of hematopoietic cell–specific antibody-drug conjugates (ADCs) as conditioning for early MPSI treatment, in which a precocious intervention is crucial. Since none of the tested setting was able to induce enough engraftment of donor’s cells to be relevant for MPSI early treatment, we tried to understand what could interfere, but we demonstrated the need for further studies prior to ADCs application in humanised models and in MPSI NSG pups. Preliminary results on increased cytokines levels after CD117-SAP in adult NSG compared to other conditioning settings were performed to evaluate impairment of inflammation and possible ADC application with anti-inflammatory drugs prior to early therapy in MPSI pups.
Motas, Mallol Sandra. "Gene therapy for the treatment of neurologic and somatic mucopolysaccharidosis type II (hunter syndrome)." Doctoral thesis, Universitat Autònoma de Barcelona, 2016. http://hdl.handle.net/10803/390961.
Full textMucopolysaccharidosis type II (MPSII), or Hunter syndrome, is an X-linked recessive lysosomal storage disease (LSD) caused by the deficiency in Iduronate-2-sulfatase (IDS), an enzyme involved in the stepwise degradation of the glycosaminoglycans (GAGs) heparan sulfate (HS) and dermatan sulfate (DS). The pathological accumulation of undegraded HS and DS in the lysosomes leads to cell dysfunction, causing severe neurologic and somatic disease. The most severe and most prevalent form of Hunter syndrome is characterized by chronic and progressive neurodegeneration of the central nervous system (CNS) and multisystem dysfunction; patients usually die during the second decade of life. To date, weekly intravenous enzyme replacement therapy (ERT) constitutes the only approved therapeutic option for MPSII. However, the inability of recombinant IDS to efficiently cross the blood-brain barrier (BBB) limits the efficacy of ERT in treating neurological symptoms. The therapy has several other drawbacks. Thus, an efficient therapy for the treatment of the neurodegeneration of MPSII disease represents a highly unmet medical need. In vivo gene therapy with adeno-associated vectors offers the possibility of lifelong therapeutic benefit following a single administration. Therefore, the present work was focused on the development of a new gene therapy approach for MPSII based on the delivery of vectors to the cerebrospinal fluid (CSF) and aimed at counteracting simultaneously the neurological and somatic pathology characteristic of the disease. Adeno-associated virus serotype 9 vectors (AAV9) containing the murine Ids gene were administered through a minimal invasive procedure to the CSF of 2-month-old MPSII mice, which already presented established pathology. The efficacy of AAV9-Ids vectors to counteract MPSII pathology after a single intra-CSF injection was evaluated 4 and 8 months after treatment. AAV9-mediated Ids gene transfer led to a significant increase in IDS activity throughout the encephalon, which resulted in full reversion of lysosomal storage lesions. In addition, correction of lysosomal dysfunction in the CNS, normalization of brain transcriptomic signature and disappearance of neuroinflammation were achieved after gene transfer. Moreover, after AAV9-Ids delivery to the CSF, vectors also transduced the liver, providing a peripheral source of the therapeutic protein that corrected storage pathology in visceral organs of treated MPSII mice. The reversion of the pathology in non-transduced somatic organs provided evidence of cross-correction by circulating enzyme. Importantly, AAV9-Ids treatment also resulted in normalization of behavioural deficits and considerably prolonged the survival of treated MPSII mice. The efficacy of the intra-CSF administration of AAV9 vectors containing the human IDS coding sequence was also evaluated in MPSII mice. One and a half months after gene transfer, a significant increase in IDS activity was documented throughout the encephalon, an in the liver and serum of treated MPSII mice. Consequently, pathological GAG content was reduced, or even normalized, in the CNS and in most somatic tissues of MPSII mice that received the vectors. Altogether, the results obtained in the present work provide a strong proof of concept that supports the clinical translation of the intra-CSF AAV9-IDS gene therapy for the treatment of Hunter patients with cognitive impairment.
Sorrentino, Nicolina Cristina. "Systemic AAV-mediated gene therapy approach to treat CNS pathology in Mucopolysaccharidosis type IIIA." Thesis, Open University, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.594745.
Full textAngermann, Alexandra [Verfasser], and Thorsten [Akademischer Betreuer] Schinke. "Skelettale Charakterisierung eines murinen Modells für Mucopolysaccharidose Typ VI / Alexandra Angermann ; Betreuer: Thorsten Schinke." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2018. http://d-nb.info/1168380952/34.
Full textMeyer, Ann [Verfasser], and Kurt [Akademischer Betreuer] Ullrich. "Der natürliche Verlauf der Mucopolysaccharidose Typ III (M. Sanfilippo) / Ann Meyer. Betreuer: Kurt Ullrich." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2012. http://d-nb.info/1030365040/34.
Full textMahon, Louise. "Objective assessment of sleep in neurodevelopmental disorders : a study of children with mucopolysaccharidosis type III." Thesis, University of Manchester, 2012. https://www.research.manchester.ac.uk/portal/en/theses/objective-assessment-of-sleep-in-neurodevelopmental-disorders-a-study-of-children-with-mucopolysaccharidosis-type-iii(35869dbd-15ba-44d7-a710-72adb2b04cd3).html.
Full textMauri, Victor [Verfasser]. "Trehalose mediated enhancement of glycosaminoglycan degradation in the lysosomal storage disorder Mucopolysaccharidosis III / Victor Mauri." Köln : Deutsche Zentralbibliothek für Medizin, 2014. http://d-nb.info/1047324342/34.
Full textYamashita, Takafumi. "C-type natriuretic peptide restores growth impairment under enzyme replacement in mice with mucopolysaccharidosis VII." Kyoto University, 2020. http://hdl.handle.net/2433/258994.
Full textAZARIO, ISABELLA MARIA REBECCA. "Neonatal transplantation of umbilical cord blood as a new therapeutic option for Mucopolysaccharidosis type I." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2018. http://hdl.handle.net/10281/199019.
Full textThe aim of this PhD project was the preclinical testing of a new possible therapeutic option for Mucopolysaccharidosis type I (MPS-I): the transplantation of umbilical cord blood (UCB) in neonatal age. MPS-I is a rare lysosomal disease due to mutations in the IDUA gene, which encodes for the lysosomal enzyme α-L-iduronidase (IDUA). The absence of IDUA activity leads to the accumulation of glycosaminoglycans (GAGs) in patients’ tissues, which causes a progressive multi-organ dysfunction, with a wide spectrum of skeletal anomalies. The first-choice therapy for MPS-I is hematopoietic stem cell transplantation (HSCT) from healthy donor, because it reduces the accumulation of substrates and it solves many clinical symptoms, but this treatment is not very effective on the skeletal defects. The aim of this thesis was to test in the murine model a novel transplantation strategy for MPS-I, combining early (neonatal) intervention and the use of murine UCB as a source. Indeed, we decided to treat our mouse model at early age, in order to prevent the anomalies, and to employ UCB cells (UCBCs) as a source for transplantation, because UCB transplantation (UCBT) has shown advantages over bone marrow transplantation in patients suffering from inherited metabolic disorders. The first result of this work was the characterization of the phenotypical and functional properties of murine hematopoietic UCBCs compared to adult bone marrow cells. Then, adult wild-type (WT) C57BL/6 mice were transplanted with UCBCs, and they reached good long-term engraftment levels, with the presence of cells of donor origin among all the hematopoietic lineages. Finally, the outcome of UCBT on neonatally-transplanted MPS-I mice was evaluated: an increase of IDUA activity was evident in the peripheral organs of high-engrafted MPS-I mice (engraftment >50%), and, consequently, GAG levels reduced. An extensive characterization of the skeletal phenotype was performed by radiographs, microCT, and histology. Radiographic images showed that MPS-I untreated mice had increased radio-opacity and diameter of the bones at 20 weeks of age, compared to WT, and these parameters were reduced in high-engrafted mice. MicroCT scans and histomorphometry revealed that the cortical region of MPS-I femurs appeared irregular, and returned to normal in treated mice with high-engraftment, confirming the benefit of neonatal UCBT on MPS-I mice. In collaboration with Alessandro Aiuti’s group at Ospedale San Raffaele-Tiget (Telethon Institute for gene therapy), a new project started with the aim of gene-correcting murine UCBCs to obtain a supra-physiological expression of IDUA enzyme. The goal is to transduce MPS-I murine UCBCs with a PGK-IDUA lentiviral vector, and to transplant gene-corrected cells into MPS-I newborns. We will verify if we can obtain in the recipients higher levels of IDUA activity than transplanting WT UCBCs, and if the outcome of gene therapy could be better than the one obtained with normal UCBCs. A method was developed to isolate hematopoietic stem and progenitor cells (HSPCs) from murine UCB and to culture them for lentiviral infection. WT untransduced UCB-HSPCs engrafted WT adult and newborn mice at high levels. We are now in the process of testing the GFP and IDUA vector on MPS-I UCBCs, to set the best conditions for their transplantation in MPS-I neonates. These results will hopefully pave the way for developing a neonatal gene therapy approach with lentivirally-corrected UCB cells in MPS-I babies.
Millat, Gilles. "Déficit en iduronate sulfatase : correction de cellules déficitaires et études fonctionnelles de mutants." Lyon 1, 1997. http://www.theses.fr/1997LYO1T237.
Full textTam, You-Cheuk. "The role of mucopolysaccharidase-producing anaerobic oral bacteria in the pathogenesis of inflammatory periodontal disease /." Thesis, McGill University, 1985. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=72044.
Full textIn the present investigation, it has been shown that anaerobic mucopolycaccharidase-producing bacteria are common inhabitants of gingival sulci of humans and that these microorganisms significantly increase in number in periodontal pockets of patients with inflammatory periodontal disease. Peptostreptococci probably are the most predominant producers of mucopolysaccharidases by virtue of their occurrence in subgingival plaque as well as the abundance of enzyme they produce. Peptostreptococci strains isolated from diseased periodontal pockets have been observed to convert from rough-colony-forming cells to smooth-colony-forming variants upon culturing in vitro. In dental plaque, hyaluronidase-producing peptostreptococci exist predominantly as the rough-colony-forming variants which produce higher amounts of hyaluronidase. Purified extracellular hyaluronidase from Peptostreptococcus strain 84H14S is different from previously reported bacterial hyaluronidases in several respects. It has different substrate specificity and optimum pH for activity. Also, the specific activity of this enzyme is much higher than any previously purified mucopolysaccharidases. Peptostreptococcus strain 84H14S is further shown to release potent cytotoxic factors into the culture medium, in addition to hyaluronidase, during its growth cycle. This may confer additional virulence to this bacterial genus in periodontal disease.
Richard, Magali. "Approches thérapeutiques non virales dans les modèles murins de mucopolysaccharidoses de type IIIA et VII." Paris 6, 2008. http://www.theses.fr/2008PA066502.
Full textYogalingam, Gouri. "Molecular characterisation of feline MPS VI and evaluation of gene therapy /." Title page, contents and abstract only, 1998. http://web4.library.adelaide.edu.au/theses/09PH/09phy54.pdf.
Full textSergijenko, Ana. "Improved lentiviral vectors for haematopoietic stem cell gene therapy of Mucopolysaccaridosis type IIIA." Thesis, University of Manchester, 2012. http://www.manchester.ac.uk/escholar/uk-ac-man-scw:176449.
Full textFroissart, Roseline. "Maturation normale de l'iduronate-2-sulfatase dans les fibroblastes humains." Lyon 1, 1995. http://www.theses.fr/1995LYO1T204.
Full textCiron, Carine. "Transfert de gène dans le système nerveux central à l'aide de vecteurs recombinants dérivés de l'Adeno-associated virus dans un modèle canin de mucopolysaccharidose de type I et chez le primate." Nantes, 2006. http://archive.bu.univ-nantes.fr/pollux/show.action?id=508fe6d0-7933-408e-b2a8-d5e3b7bc6d28.
Full textAdeno-associated viral vectors (AAV) are nonpathogenic for humans and allow for the long term expression of transgenes in the central nervous systeme (CNS). Mucopolysaccaridosis type I is a lysomal storage disorder. The most severe form of MPS I is characterised by severe neuronal symptoms. We evaluated the efficacy of gene replacement therapy into the CNS of a canine model of MPS I using an rAAV5 vector. Four stereotaxic injections prevented glycoaminoglycan and secondary ganglioside accumulations. The pattern of transduction of AAV serotypes has been described predominantly in rodents. In addition to this study, we evaluated the transduction pattern of three AAV serotypes after intracerebral injection in the CNS of nonhuman primates: rAAV1, rAAV2, and rAAV5. RAAV1 seems to be the most efficient serotype in the CNS of nonhuman primates. In these studies, we have shown the feasibility of gene therapy with AAV vectors in the brain of large animal models
Sachot, Sylvain. "Étude du trans-épissage comme outil de thérapie génique dans le modèle canin de la mucopolysaccharidose de type VII." Nantes, 2009. https://archive.bu.univ-nantes.fr/pollux/show/show?id=aa099ce6-00b8-4284-84b9-e794ed82ede9.
Full textAmong corrective strategies in gene therapy, trans-splicing allows the reprogramming, at the pre-messenger RNA level, of a mutant sequence by an exogenous and normal sequence carried by a « PTM » in a reaction controlled by the spliceosome. In this study, we evaluated the feasibility of trans-splicing in the canine model of mucopolysaccharidosis VII. We tested different PTM and different adjuvant molecules, the U7 snRNA and the bifunctional RNA. Our results show that in an artificial minigene context, trans-splicing allows the reprogramming of the GusB transcript, as seen at the molecular and at the protein levels. However, things are more difficult in the natural context. In this environment, PTM are able to react with their target, but the efficiency is the major limiting factor. Thus, even if it was possible to detect trans-splicing resulting transcript, particularly in the presence of the U7 snRNA and of the bifunctional RNA, we could not detect trans-splicing resulting protein in this environment. This study, like others, points the difficulty to manipulate trans-splicing in the gene therapy protocols
Ciron, Carine Moullier Philippe Colle Marie-Anne. "Transfert de gène dans le système nerveux central à l'aide de vecteurs recombinants dérivés de l'Adeno-associated virus dans un modèle canin de mucopolysaccharidose de type I et chez le primate." [S.l.] : [s.n.], 2006. http://castore.univ-nantes.fr/castore/GetOAIRef?idDoc=38056.
Full textDierenfeld, Ashley Dawn. "Enzyme replacement therapy treatment from birth increases therapeutic efficacy and generates tolerance to enzyme in canine mucopolysaccharidosis type I." [Ames, Iowa : Iowa State University], 2009. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:1473198.
Full textMumford, Rachel Anne. "Circadian rhythms, sleep and behaviour in intellectual and developmental disabilities : a systematic review of sleep and challenging behaviour and actigraphic assessment of circadian functioning in MPS III (Sanfilippo syndrome)." Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/circadian-rhythms-sleep-and-behaviour-in-intellectual-and-developmental-disabilities-a-systematic-review-of-sleep-and-challenging-behaviour-and-actigraphic-assessment-of-circadian-functioning-in-mps-iii-sanfilippo-syndrome(a42b0492-2049-4cf6-9eae-8a7c6fdcf36a).html.
Full textMadoui, Abdelmadjid. "Contribution à l'étude des modifications de la prostate provoquées par certains anabolisants (Acetate de trenbolone, Zeranol, 17 ß Oestradiol) chez le veau." Toulouse, INPT, 1986. http://www.theses.fr/1986INPT008A.
Full textAbily-Donval, Lénaïg. "Exploration des mécanismes physiopathologiques des mucopolysacharidoses et de la maladie de Fabry par approches "omiques" et modulation de l'autophagie. Urinary metabolic phenotyping of mucopolysaccharidosis type I combining untargeted and targeted strategies with data modeling Unveiling metabolic remodeling in mucopolysaccharidosis type III through integrative metabolomics and pathway analysis." Thesis, Normandie, 2019. http://www.theses.fr/2019NORMR108.
Full textLysosomal diseases caused by quantitative or qualitative hydrolase or transporter defect induce multiorgan features. Some specific symptomatic treatments are available but they do not cure patients. Pathophysiological bases of lysosomal disease are poorly understood and cannot be due to storage only. A better knowledge of these pathologies could improve their management. The first aim of this study was to apply “omics” strategies in mucopolysaccharidosis and in Fabry disease. This thesis allowed the implementation of an untargeted metabolomic methodology based on a multidimensional analytical strategy including high-resolution mass spectrometry coupled with ultra-high-performance liquid chromatography and ion mobility. Analysis of metabolic pathways showed a major remodeling of the amino acid metabolisms as well as oxidative stress via glutathione metabolism. In Fabry disease, changes were observed in expression of interleukin 7 and FGF2. The second study focused on modulation of autophagy in Fabry disease. In this work, we have shown a disruption of the autophagic process and a delay in enzyme targeting to the lysosome in Fabry disease. Autophagic inhibition reduced accumulation of accumulated substrate (Gb3) and improved the efficiency of enzyme replacement therapy. This work allowed a better knowledge of the physiopathological mechanisms implicated in lysosomal diseases and showed the complexity of lysosome. These data could ameliorate management of these disease and are associated with hope for patients