Dissertations / Theses on the topic 'Maladies de surcharge lysosomale'
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Hippert, Claire. "Etudes de transfert de gène pour une maladie de surcharge lysosomale, la cystinose." Montpellier 2, 2009. http://www.theses.fr/2009MON20118.
Full textCystinosis is a lysosomal storage disorder characterised by a defective lysosomal cystine efflux. The causative gene, CTNS, encodes the lysosomal cystine transporter, cystinosin. Storage of cystine, which forms crystals at high levels, disrupts the function of different organs at different rates. Cysteamine, the only treatment currently available to reduce lysosomal cystine levels, has dramatically improved the life of patients. However, due to its administration constraints and side effects, we explored the feasibility of viral-mediated CTNS gene therapy to reduce cystine levels in cystinosin-deficient (Ctns-/-) mice. The main part of my PhD was concentrated on in vivo gene transfer studies to the liver using CTNS-expressing human adenovirus vectors (hAd). This work provided for the first time the proof-of-concept that viral-mediated CTNS gene transfer can correct a lysosomal transport defect, but suggests that, in the case of cystinosis, it could be preventive but not curative in some tissues. Rather than attempting a mulisystemic gene therapy to cystinosis, we specifically concentrated on treating the ocular and CNS anomalies, which are incapacitating and have the potential to be life-threatening. Thus, along this line, we characterised these anomalies in Ctns-/- mice : we showed that they mimic those of patients and, in parallel, generated a temporospatial guide to their appearance, an essential tool for testing novel ocular and CNS cystine-depleting therapies. The next step of this work was to begin gene transfer studies in these structures using more clinically relevant vectors than hAd vector: an helper dependant canin adenovirus and an adeno-associated virus
Ruivo, Raquel. "Molecular physiology and pathophysiology of two lysosomal transporters : sialin and cystinosin." Paris 11, 2009. http://www.theses.fr/2009PA11T083.
Full textAndrzejewska, Zuzanna. "Study of the lysosomal trafficking of cystinosin and its role in the mTORC1 pathway." Thesis, Paris 5, 2013. http://www.theses.fr/2013PA05T061.
Full textPas de résumé en anglais
Denard, Jérôme. "Développement d'une approche de thérapie génique pour l'amyotrophie spinale avec épilepsie myoclonique progressive." Electronic Thesis or Diss., université Paris-Saclay, 2023. https://www.biblio.univ-evry.fr/theses/2023/interne/2023UPASL144.pdf.
Full textSpinal muscular atrophies are a heterogeneous group of disorders characterized by spinal cord α-motor neuron degeneration, leading muscle weakness and atrophy. The most common form is associated to mutations in the SMN1 gene, for which a gene therapy product obtained marketing approval. Another form of spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME), is due to mutations in the ASAH1 gene encoding a lysosomal enzyme,the acid ceramidase (ACDase). The life expectancy of patients with SMA-PME does not exceed adolescence. Some mutations in this same gene can cause Farber disease (FD), with the most severe forms causing death of patients before the age of 2 years due to severe multisystemic damage. SMA-PME and FD are ultra-rare lysosomal storage diseases. ACDase catalyzes the bioactive lipid ceramide into sphingosine and fatty acid. Due to the deficiency of enzyme activity, ceramides accumulate inside lysosomes causing serious dysfunctions in several organs. A therapeutic approach based on hematopoietic stem cell transplantation was previously tested in Farber patients but did not prevent neurological deterioration over time. The generation of mouse models of ACDase deficiency, in particular the Asah1P361R/P361R model that recapitulates the signs of Farber disease, has allowed a better understanding of the pathophysiology of acid ceramidase deficiency in tissues and the evaluation of different therapeutic approaches. Enzyme replacement therapy and gene therapy using a lentiviral vector extended the survival of mutant animals by several weeks, but did not correct the neurological signs of the disease. Since there is no curative treatment for patients, the main goal of my thesis project was to develop an efficacious gene therapy approach using an AAV vector. Intravenous administration of an AAV9-ASAH1 vector in Asah1P361R/P361R mice at pre- and symptomatic stages of the disease was able to prolong the lifespan and correct the phenotype. This approach provided proof of concept that generalized restoration of ASAH1 gene expression achieves a therapeutic effect in a severe mouse model of acid ceramidase deficiency. These results prompted us to perform a dose escalation study in Asah1P361R/P361R mice to determine the minimum effective dose of this vector. Three doses of AAV9-ASAH1 were administered intravenously in mutant mice at a late stage of the disease and the effect was analyzed at the clinical, molecular and histological level for a 6-month period. We identified a vector dose able to correct the phenotype and to avoid macrophage infiltrates in tissues, including the central nervous system. Intracerebroventricular administration (ICV) of the AAV9-ASAH1 vector in neonatal mutant mice was also evaluated to investigate the efficacy of this direct route of administration in correcting the neurological signs of the disease. The results show that systemic injection of the AAV9-ASAH1 vector was able to correct the whole-body phenotype of Asah1P361R/P361R mutant mice, whereas preliminary results indicate that ICV administration of the vector is efficacious in preventing mainly the neurological signs of the disease. This thesis work paves the way for clinical translation of this gene therapy in patients with Farber and SMA-PME diseases
Roy, Elise. "Cell disorders in lysosomal storage diseases." Phd thesis, Université René Descartes - Paris V, 2012. http://tel.archives-ouvertes.fr/tel-00683248.
Full textBarr, Caroline. "Évaluation de l'excrétion urinaire d'un biomarqueur pour la maladie de Fabry, le globotriaosylcéramide (Gb[indice inférieur 3]), chez des enfants normaux de la naissance à 6 mois." Mémoire, Université de Sherbrooke, 2009. http://savoirs.usherbrooke.ca/handle/11143/4010.
Full textWoronoff, Anne-Sophie. "Cystinose juvenile : maladie de surcharge lysosomiale , a propos d'une observation familiale avec atteinte renale." Besançon, 1994. http://www.theses.fr/1994BESA3084.
Full textDa, Silva Afitz. "Glycovecteurs pour le ciblage thérapeutique d'une maladie rare lysosomale : la maladie de Pompe." Thesis, Montpellier, 2017. http://www.theses.fr/2017MONTT001.
Full textOn 53 known rare lysosomal diseases, only 8 can be treated by enzyme replacement therapy with more or less efficiency. There is therefore a need to develop new treatments but also to better characterize these diseases. During this thesis, we focused on Pompe disease which results from the absence or deficiency of the lysosomal enzyme alpha-glucosidase acid (GAA), responsible for the degradation of glycogen in glucose in many tissues. Currently only the infantile form of this disease can be treated while the juvenile/adult form is slightly improved by Myozyme® treatment. This thesis aimed to devel a new enzyme replacement therapy which could prevent the progression of the disease and satisfactorily treat the late onset form of the disease. To do that, we used monosaccharide derivatives “Mannose-6-phosphate analogues (M6P) Functionalized on Aglycone (AMFA)”, which were grafted onto human recombinant GAA (rhGAA) in order to improve its lysosome addressing obtaining the rhGAA-AMFA.A first in vitro study on adult patient fibroblasts showed that the addition of AMFA to rhGAA, produced in Sf9 insect cells, significantly improved its affinity for the M6P receptor (RM6P), its internalization and activity. It was also more efficient on the GAA-/- Pompe mouse model compared to current treatment (Article 1). Then, we demonstrated for the first time the efficiency of rhGAA-AMFA produced in CHO cells in aged mice model. These results suggest the possibility to use this neo-enzyme in the treatment of the adult form that still resists to treatment (Article 2). Finally, the addition of AMFA allows a complete maturation of rhGAA into its active form in myoblasts and myotubes of adult patients and in the quadriceps of aged mice Pompe model. This was not observed for Myozyme® (Article 3). In this thesis we have also demonstrated that novel disaccharide analogues with a better affinity than monosaccharides for RM6P can efficiently target GAA for the treatment of Pompe disease. A patent has been filed on these results (Patent PCT / FR2016 / 052339).In conclusion, this work has led to the development of a new technology more efficient in targeting lysosomal enzymes by mean of new synthetic analogues. An orphan drug designation for the recombinant human acid alpha-glucosidase conjugated with mannose-6-phosphate analogues was obtained on the basis of this work at the European Medicines Agency for the treatment of Pompe disease (EMA/OD/098/16).Key words: lysosomal diseases, Pompe disease, enzyme replacement therapy, mannose 6-phosphate receptor
Hilaire, Nathalie. "Métabolisme cellulaire des lipides neutres cytoplasmiques et myopathie à surcharge lipidique multisystémique." Toulouse 3, 1994. http://www.theses.fr/1994TOU30051.
Full textTardy, Claudine. "Rôle des protéases lysosomales dans l'apoptose : relation avec la physiopathologie des maladies lysosomales." Toulouse 3, 2004. http://www.theses.fr/2004TOU30143.
Full textLysosomes are cellular organelles which contain numerous enzymes for degradation of macromolecules. For many years, they have been considered as suicide bags that would release unspecific digestive enzymes after uncontrolled cell damage. However, some lysosomal proteases have been recently suggested to act as cell death mediators. This work aimed at analyzing the role of lysosomal proteases in apoptosis. We investigated the implication of lysosomal proteases in cell death by using fibroblasts isolated from patients with either I-cell disease, a lysosomal targeting defect, or neuronal ceroid lipofuscinoses (due to a single lysosomal defect). We have shown that these fibroblasts are partially resistant to TNF-induced cell death as compared to control cells. Our results indicate that Tripeptidyl peptidase 1 (TPP1) and Palmitoyl-protein thioesterase 1 (PPT1), two lysosomal hydrolases, may contribute to TNF-induced apoptosis
Bastie, Diane de la. "Modifications de l'expression du génome cardiaque sous l'effet d'une surcharge de travail hémodynamique." Paris 11, 1989. http://www.theses.fr/1989PA112161.
Full textJutras, Annick. "Variabilité de la fréquence cardiaque lors d'une surcharge lipidique alimentaire chez des hommes avec obésité viscérale." Thesis, Université Laval, 2010. http://www.theses.ulaval.ca/2010/27692/27692.pdf.
Full textBizou, Mathilde. "Identification et participation des macrophages dans la régulation du système lymphatique cardiaque au cours du remodelage de surcharge de pression." Thesis, Toulouse 3, 2018. http://www.theses.fr/2018TOU30098.
Full textThe lymphatic system has recently emerged as an important regulator of the cardiac interstitial fluid compartment and function. Experimental obstruction of lymphatic vessel leads to cardiac œdema, myocardial stiffness, fibrosis and ventricle dysfunction. Following myocardial infarction, stimulation of lymphangiogenesis was found to reduce fibrosis and inflammation and to improve cardiac function. Macrophages have been largely described as important contributors of lymphangiogenesis in inflammatory situations such as cancer. Recently, genetic fate mapping demonstrated that distinct populations of macrophages coexist in the adult heart. In addition to monocyte derived-macrophages that massively colonize injured heart, a subpopulation of tissue-resident macrophages that originates from embryonic precursors persists into adulthood by means of local self- renewal. To date the distinct involvement of cardiac macrophage subpopulations in cardiac lymphatic remodeling and heart failure progression induced by pressure overload is largely unknown. In our study, we observed that expression of Lyve-1 identifies a resident macrophage subset abundant in mouse heart. This Lyve-1 positive macrophage subset decreased rapidly in cardiac remodeling induced by chronic pressure overload. In addition, the number of cells found in heart was positively correlated with the preservation of cardiac lymphatic network and function after transverse aortic constriction (TAC). Blocking recruitment of monocyte derived macrophages expanded Lyve-1 positive macrophages, attenuated cardiac lymphatic remodeling and contractile dysfunction of pressure overloaded heart. Lyve-1 positive macrophages express pro-lymphangiogenic factors and sustain lymphangiogenesis in vitro and in vivo. In conclusion, resident macrophage subset expressing the Lyve-1 receptor participates to maintain cardiac function after chronic pressure overload by mechanisms that may involve the preservation of cardiac lymphatic system. These results provide insight into the regulation of lymphatic homeostasis by tissue resident macrophage during heart failure induced by pressure overload
Lambert, Virginie. "Thérapie cellulaire par progéniteurs cardiaques issus de cellules souches embryonnaires dans un modèle porcin de dysfonction ventriculaire droite par surcharge chronique." Paris 5, 2009. http://www.theses.fr/2009PA05P639.
Full textThe long term prognosis of some congenital heart diseases may be impaired related to severe right ventricular (RV) dysfunction and conventional therapies give poor results. Cell therapy may be an alternative therapeutic approach. The aims of this study were 1/ to create an experimental model of RV dysfunction secondary to chronic overload as observed in congenital heart diseases, 2/ to apply on this failed RV a cell therapy using cardiac progenitors derived from human embryonic stem cells. We have characterized in a large animal a model of RV dysfunction secondary to a combined chronic overload using a surgical procedure reproducing the RV outflow tract diseases as observed after repair in tetralogy of Fallot. After 4 months, we have observed the various aspects of RV dysfunction: hemodynamic with an impairment of myocardial contractility, electrophysiological with an increasing of duration of both QRS and action potential and histological with a myocardial remodelling at the first stage. In this model of RV dysfunction, we have applied cell therapy and injected into multiple sites of RV myocardium cardiac progenitors derived from human embryonic stem cells. We have observed an improvement of myocardial contractility and a stabilization of the deleterious effects of the chronic overload on cardiac function. No ventricular arrhythmia occurred and no teratoma was detected. This first attempt of cell therapy using cardiac progenitors is encouraging and may be an interesting innovative approach to treat RV dysfunction secondary to chronic overload
Walsh-Wilkinson, Élisabeth. "Dimorphisme sexuel dans la réponse myocardique à une surcharge de volume : observations chez le rat ayant une régurgitation de la valve aortique." Master's thesis, Université Laval, 2020. http://hdl.handle.net/20.500.11794/66570.
Full textThe incidence of cardiovascular disease differs between men and women. Symptoms, disease’s evolution, response to treatment and even care are different depending on the sex. Cardiac hypertrophy (HC) is the heart's response to sustained and significant hemodynamic overload. HC can be concentric (thickening of the walls) or eccentric (dilation of the chamber). Mechanisms involved in the sexual dimorphism of HC are still poorly understood. Our team is interested in a model of severe aortic valve regurgitation (RA) in rats. We have already shown that women’s heart has a more concentric remodeling, a better capillary density and a gene profile of mitochondrial function and energy metabolism closer to normal, compared to males. We were first interested in the involvement of sex hormones in this sexual dimorphism. Echocardiographic data and tissue analyze show that androgen deficiency in RA males reduces hypertrophic response, improves cardiac function and tends to improve survival. Estrogen loss is not associated with significant hypertrophic changes in RA females. We then studied the effect of valsartan, a treatment targeting the renin angiotensin system (RAAS), a highly activated hormonal pathway in HC. Inhibition of RAAS activity prevents concentric hypertrophy in female’s heart in the early weeks of RA, whereas it has little effect in RA males. Finally, we were interested in the morphological and functional evolution of the heart in RA rats. Echocardiographic analysis shows that RA females’ left ventricle rapidly loses contractile function, circumferential deformation capacity, and changes its normal elliptical shape, compared to males. The results presented here improve our understanding of sexual differences in HC.
Laurant, Pascal. "Etude des effets de la surcharge chronique en magnésium sur le fonctionnement de l'appareil cardiovasculaire au cours de l'hypertension minéralocorticoi͏̈de DOCA + NaCl chez le rat mâle." Besançon, 1990. http://www.theses.fr/1990BESA3702.
Full textEl, Alaoui-Talibi Zaïnab. "Contribution à l'étude du métabolisme lipidique dans les cœurs hypertrophiés de rats." Paris 11, 1989. http://www.theses.fr/1989PA112196.
Full textCamps, Bres Flora. "Synthèse d'aminocyclitols, inhibiteurs potentiels de glycosidases lysosomales, via des aldolases." Phd thesis, Université Blaise Pascal - Clermont-Ferrand II, 2010. http://tel.archives-ouvertes.fr/tel-00629666.
Full textBifsha, Panojot. "Implication de la voie de dégradation ubiquitine-dépendante dans la pathologie des maladies de surchage lysosomale." Thèse, 2005. http://hdl.handle.net/1866/15199.
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