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Trimby, Christopher Matthew. "STRATEGIES FOR TARGETING LENTIVIRAL VECTORS". UKnowledge, 2011. http://uknowledge.uky.edu/gradschool_diss/157.
Pełny tekst źródłaIngrao, Dina. "Etude de l'étape d'entrée des vecteurs lentiviraux dérivés du VIH-1 dans les cellules hématopoïétiques humaines". Thesis, Evry-Val d'Essonne, 2013. http://www.theses.fr/2013EVRY0021/document.
Pełny tekst źródłaLentiviral vectors (LV) are used for various gene transfer applications, notably for hematopoietic gene therapy, but methods are lacking to precisely evaluate parameters that control the efficiency of transduction in relation with the entry of vectors into target cells. We adapted a fluorescence resonance energy transfer (FRET)-based HIV-1 fusion assay to measure the entry of non-replicative recombinant LV in various cell types, including primary human hematopoietic stem and progenitor cells, and to quantify the level of transduction of he same initially-infected cells. The assay utilizes recombinant LV containing betalactamase (BLAM)-Vpr chimeric proteins (BLAM-LV) and encoding a truncated form of thelow affinity nerve growth factor receptor (DELTA-NGFR). This LV-based fusion/transduction assay is a dynamic and versatile tool, revealing for instance the extent of lentiviral post-entry restrictions occuring in cells of hematopoietic origin. The assay also shows that transduction enhancers like Vectofusin®-1 or Retronectin® can partially relieve this post-entry block but their effects differ in the way to promote LV entry. Furthermore, our results show that Vectofusin®-1 acts at the entry step by promoting the adhesion and the fusion between lentiviral and cellular membranes. In conclusion, one such assay should be useful to study hematopoietic post-entry restrictions directed against LV and should allow improvements in various LV-based gene therapy protocols
Thomas, Joan Helen. "Studies in gene transfer using pseudotyped lentiviral vector systems". Thesis, University of Cambridge, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.621818.
Pełny tekst źródłaGelinas, Jean-Francois. "Enhancement of lentiviral vector production through alteration of virus-cell interactions". Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:9921b8b4-e2b5-4eec-9efc-6036765c8d55.
Pełny tekst źródłaZhang, Bing. "Lentiviral vector-mediated gene transfer in vitro and in vivo /". St. Lucia, Qld, 2004. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe18024.pdf.
Pełny tekst źródłaBooth, C. A. "Lentiviral vector mediated gene therapy for X-linked lymphoproliferative disease". Thesis, University College London (University of London), 2012. http://discovery.ucl.ac.uk/1356299/.
Pełny tekst źródłaMacdonald, D. "Lentiviral vector vaccines for T-cell-mediated protection against influenza". Thesis, University College London (University of London), 2014. http://discovery.ucl.ac.uk/1417882/.
Pełny tekst źródłaOakland, Mayumi. "Improving lentiviral vector-mediated gene transfer by understanding cellular barriers". Diss., University of Iowa, 2013. https://ir.uiowa.edu/etd/4709.
Pełny tekst źródłaMekkaoui, Leila. "Lentiviral vector purification using genetically encoded biotin mimic in packaging cell". Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10053191/.
Pełny tekst źródłaFIRRITO, CLAUDIA. "Targeted Gene Correction and Reprogramming of SCID-X1 Fibroblasts to Rescue IL2RG Expression in iPSC-derived Hematopoietic Cells". Doctoral thesis, Università degli Studi di Milano-Bicocca, 2015. http://hdl.handle.net/10281/94656.
Pełny tekst źródłaGene replacement by integrating vectors has been successfully used to treat several inherited diseases, such as Lysosomal Storage Disorders (LSD), Thalassemia and Primary Immunodeficiencies (PIDs). X-linked Combined Immunodeficiency (SCID-X1) is a fatal monogenic disorder, caused by mutation of the Interleukin 2 Receptor common γ-chain (IL2RG) gene. For SCID-X1, the early clinical studies have clearly shown the therapeutic potential of integrating vector based gene replacement therapy, which achieved efficient lymphoid reconstitution thanks to the selective growth advantage of the genetically modified cells. However, these studies also highlighted the potential risk of insertional mutagenesis due to random integration of the vector into the host cell genome and to unregulated transgene expression, thus calling for the development of safer gene therapy approaches. Here, by combining the Zinc Finger Nuclease (ZFNs) technology to induce site-specific DNA double-strand breaks (DSB) and of Integrase-Defective Lentiviral Vector (IDLV) to deliver a corrective donor template, we exploited Homology Driven Repair (HDR) to correct SCID-X1 mutation in situ, restoring both physiological expression and function of the IL2RG gene . By knocking-in a corrective IL2RG cDNA transgene downstream of its endogenous promoter in B-lymphoblastoid cells, which constitutively express IL2RG, and in primary T-lymphocytes, which requires IL2RG for their survival and growth, we provide evidence of physiologic activity of the gene-edited IL2RG gene. By including an excisable GFP- or a Puromycin Resistance (PuroR) expression cassette downstream of the corrective cDNA, we coupled correction with exogenous selection of corrected SCID-X1 primary fibroblasts, which do not physiologically express IL2RG, and obtained an enriched population of gene-corrected cells. We then reverted this population to pluripotency by using a novel reprogramming vector that expresses OCT4, SOX2, KLF4 and microRNA cluster 302-367 to obtain a potentially unlimited source of gene-corrected induced pluripotent stem cells (iPSC). We thus generated several gene-corrected bona-fide iPSCs, as confirmed by molecular analyses for targeted integration, which were characterized for their pluripotent state. IDLV-mediated transient delivery of the Cre-recombinase resulted in the co-excision of the reprogramming vector together with the selector cassette, thus allowing the generation of several gene-corrected, reprogramming-factor free iPSCs with normal karyotypes. Finally, by differentiating corrected iPSC to T-lymphoid progenitor cells, which are lacking in SCID-X1 patients, and showing a selective growth advantage of those derived from corrected iPSCs, we provide evidence of the functional correction of the IL2RG mutant allele. Overall these data demonstrate the feasibility of our targeted gene editing strategy, which couples gene correction with cell reprogramming to generate disease-free IPSC, thus paving the way for the development of novel and safer therapeutic approaches for SCID-X1.
Giorgi, Marie. "Optimisation de la stratégie de thérapie génique par vecteur lentiviral pour la β-thalassémie". Thesis, Sorbonne Paris Cité, 2019. http://www.theses.fr/2019USPCC047.
Pełny tekst źródłaΒ-thalassemia is one of the most frequent genetic disease in the world. It results from the defective production of -globin and a major disequilibrium between beta and alpha globin chains. Gene therapy of hematopoietic stem cells is an innovative and promising strategy for the patient recovery. A lentiviral vector delivering the β-globin chain had recently proved its efficacy upon clinical trials. We have worked to improve this strategy using several approaches. Thanks to a selection system, combining the puromycin resistant gene and the therapeutic transgene, we have succeeded in extending the proportion of genetically modified cells. Through the introduction of a shRNAmir targeting the α-globin chain in the lentiviral vector, we have observed a high improvement of the beta to alpha globin ratios, in fetal and in patient’s erythroid cells. In addition, we have developed and analyzed several strategies in order to reduce the insertional mutagenesis linked to the use of lentiviral vectors. We did not obtain convincing results to target lenviral vector into expected harbors but the vector insertion profile was successfully modified. In summary, this work will contribute to the enhancement of the efficacy of the gene therapy treatment strategy of β-thalassemic patients
Zhang, Xinyu. "Expression of polysialic acid mediated by lentiviral vector to promote axonal regeneration". Thesis, Queen Mary, University of London, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.443583.
Pełny tekst źródłaLangford-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.
Pełny tekst źródłaSPINOZZI, GIULIO. "Anti-Cancer Drug Resistance Causal Modeling from Lentiviral-Vector Integration Site Studies". Doctoral thesis, Università degli Studi di Milano-Bicocca, 2017. http://hdl.handle.net/10281/151647.
Pełny tekst źródłaEvolution plays a key role in Cancer as the result of the accumulation of genetic alterations, which provide selective advantages to a tumor cell, allowing resistance to anti-cancer drugs. Unfortunately, however, the identification of the driver mutations and thus the mechanisms underlying anti-cancer drug resistance (ACDR) still remains a challenge. We previously demonstrated that lentiviral vectors, when properly modified, might integrate near specific genes, alter their expression and induce cancer or ACDR in vivo and in vitro. The analysis of vector-cellular genomic junctions in tumor or ACDR cells allowed identifying causative genes of HER2+ breast cancer cell line using a statistical approach defined Common Insertion Sites (CISs) that highlight genomic regions targeted at significantly higher frequency than expected by a random distribution. The reconstruction of cumulative cancer progression from CISs genes has not been yet addressed and may produce causative gene networks. The aim of this project is studying anti-cancer drug resistance from exclusive and co-occurring genes using cumulative cancer progression from our cell line CISs genes and investigating the relation between them. Bioinformatics tools aimed at inferring cancer progression models, in terms of selective advantage relation among relevant genomic alteration from cross-sectional data (Next Generation Sequencing platforms), would allow identifying specific combinations of targeted drugs to overcome the occurrence of resistance. In a new context of vector Integration Sites (ISs), I developed an integrated bioinformatics workflow composed of: (i) an updated and more accurate version of VISPA (Vector Integration Site Parallel Analysis), a pipeline for automated ISs identification and annotation based on a distributed environment with a simple web based interface; (ii) identification of the CISs with a sliding window approach; (iii) a new statistical tool, CAncer PRogression Inference (CAPRI), to infer selective advantage relations among various mutational events in cancer cell genomes, mostly in relation with drug-resistance. The model is based on probabilistic causation and is able to reconstruct our cancer progression Direct Acyclic Graphs (DAGs), involving the CIS genes. With the use of GeneMANIA (http://www.genemania.org) and Enrichr (http://amp.pharm.mssm.edu/Enrichr), I studied the protein-protein interaction, Gene Ontology and Pathway relations between selected genes, collecting and visualizing results in gene networks. By applying our new method to the published ISs dataset from the two cell lines, I was able to generate progression models involving relevant genes (confirming that these are not mutually exclusive genes, by Mutex), which are consistent with previously validated results, confirming the role of PIK3CA-ERBB2 genes in ACDR. Unfortunately, one of the two cell line has a low quality samples. For this reason, CAPRI was not able to generate the progression DAG. I generated the progression DAG for the other cell line, BT474, pre-treatment and post-treatment with lapatinib respectively. The last step is to investigate the relations between genes, produced by the model, trying to find some useful new interactions and confirmations for ACDR studies (i.e. SUMO1-ERBB2-PIK3CA-CSMD3). New insertional mutagenesis data from lung cancer cell lines aimed to induce ACDR in vivo and in vitro are ongoing and will allow to validate and/or identify novel cancer progression models, as well as possible combinatorial therapies.
Galvan, Laurie. "Étude de l'implication potentielle des marqueurs du striatum dans la maladie de Huntington". Thesis, Paris 11, 2011. http://www.theses.fr/2011PA11T024.
Pełny tekst źródłaHuntington's disease (HD) is an incurable inherited neurodegenerative disease. HD iscaused by a mutation in the HD gene coding huntingtin (htt). This mutation leads to anexpanded polyglutamine tract (polyQ) in the protein which is toxic to neurons. Although thehtt is ubiquitously expressed in the central nervous system, the first area which degeneratesis the striatum. A pattern of genes selectively expressed into the striatum may confer itsvulnerability to mutated htt. We have studied the modifying effects of five newly identifiedstriatal markers against the toxicity induced by mutated htt using lentiviral strategy in miceand histological approaches. For one of these markers, Double Cortin Kinase Like 3(DCLK3), we have further determined their cellular localization and the potential mechanismsunderlying their neuroprotector effects. The present work led to a better understanding of thefunction of the newly identified markers in the striatum and their potential roles in thepreferential vulnerability of the striatum in HD
Coleman, Jason Edward. "Efficient transduction and targeted expression of lentiviral vector transgenes in the developing retina". [Gainesville, Fla.]: University of Florida, 2003. http://purl.fcla.edu/fcla/etd/UFE0000665.
Pełny tekst źródłaLimberis, Maria. "A lentiviral gene transfer vector for the treatment of cystic fibrosis airway disease". Title page, synopsis and list of contents only, 2002. http://web4.library.adelaide.edu.au/theses/09PH/09phl735.pdf.
Pełny tekst źródłaNilsson, S. M. "Process development of lentiviral vector expression, purification and formulation for gene therapy applications". Thesis, University College London (University of London), 2016. http://discovery.ucl.ac.uk/1485725/.
Pełny tekst źródłaHino, Shinjiro. "Sea Urchin Insulator Protects Lentiviral Vector from Silencing by Maintaining Active Chromatin Structure". Kyoto University, 2004. http://hdl.handle.net/2433/147507.
Pełny tekst źródłaParker, Douglas George Anthony, i park0290@flinders edu au. "Lentivirus-mediated gene expression in corneal endothelium". Flinders University. Medicine, 2008. http://catalogue.flinders.edu.au./local/adt/public/adt-SFU20081204.094431.
Pełny tekst źródłaMcLean, Rebecca Kathryn. "Development of a novel lentiviral vaccine vector and characterisation of in vitro immune responses". Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/31135.
Pełny tekst źródłaShinoda, Yasuhiko. "Efficient transduction of cytotoxic and anti-HIV-1 genes by a gene-regulatable lentiviral vector". Kyoto University, 2010. http://hdl.handle.net/2433/120584.
Pełny tekst źródłaDresch, Christiane. "Antigen-specific tolerance induction by transcriptional targeting of dendritic cells with a novel lentiviral vector". Diss., kostenfrei, 2008. http://edoc.ub.uni-muenchen.de/9310/.
Pełny tekst źródłaHaynes, Soraya. "Construction of a novel bat coronavirus glycoprotein pseudotyped lentiviral vector and analysis of cell tropism". Thesis, Haynes, Soraya (2019) Construction of a novel bat coronavirus glycoprotein pseudotyped lentiviral vector and analysis of cell tropism. Honours thesis, Murdoch University, 2019. https://researchrepository.murdoch.edu.au/id/eprint/54215/.
Pełny tekst źródłaSantoni, de Sio Francesca Romana. "Critical parameters and molecular analysis of lentiviral vector-mediated gene transfer into human haematopoietic stem cells". Thesis, Open University, 2006. http://oro.open.ac.uk/54821/.
Pełny tekst źródłaCamacho, Emely. "Optimization of Lentivirus Production for Cancer Therapy". Thesis, Uppsala universitet, Institutionen för medicinsk biokemi och mikrobiologi, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-164715.
Pełny tekst źródłaFrank, Sander B., Veronique V. Schulz i Cindy K. Miranti. "A streamlined method for the design and cloning of shRNAs into an optimized Dox-inducible lentiviral vector". BIOMED CENTRAL LTD, 2017. http://hdl.handle.net/10150/623280.
Pełny tekst źródłaCATTANEO, STEFANO. "Combinatorial gene therapy for epilepsy". Doctoral thesis, Università Vita-Salute San Raffaele, 2022. http://hdl.handle.net/20.500.11768/128275.
Pełny tekst źródłaL'epilessia è una malattia neurologica caratterizzata da una persistente predisposizione a generare crisi, che colpisce circa l'1% della popolazione mondiale. Circa il 30% dei pazienti epilettici sono resistenti ai farmaci, quindi refrattari ai farmaci antiepilettici attualmente disponibili (AED). Meno del 10% di questi pazienti resistenti ai farmaci sono eleggibili per la chirurgia, spesso a causa di foci epilettici generalizzati o multipli, o a causa della vicinanza del focus epilettico alle aree cerebrali eloquenti. Pertanto, la terapia genica può rappresentare un approccio fattibile. Il neuropeptide Y (NPY) può agire come un anticonvulsivo endogeno. L'espressione di NPY è aumentata sia nelle sezioni ippocampali di roditori che in quelle di campioni chirurgici umani di epilessia del lobo temporale, nonostante la forte perdita di interneuroni GABAergici a livello dell’ilo. Pertanto, la terapia genica basata su NPY può rappresentare un nuovo approccio per il trattamento delle epilessie focali. Idealmente, tuttavia, tali vettori dovrebbero contenere più elementi (almeno NPY e Y2R guidati da promotori appropriati). In passato, il nostro laboratorio ha fatto grandi progressi nel campo dei vettori virali basati su HSV-1. Abbiamo quindi mirato a combinare il potenziale dei vettori HSV di ospitare DNA di grandi dimensioni, e la complessità del sistema NPY, per creare una cassetta terapeutica combinatoria "ideale". Tuttavia, le preoccupazioni residue in merito alla sicurezza della nostra nuova generazione di vettori basati su HSV-1 (chiamati J∆NI8) ci hanno spinto a valutare i profili di sicurezza ed efficacia in vitro per valutare l’effetto dell’infezione sulle proprietà elettrofisiologiche in neuroni primari. Sorprendentemente e in maniera deludente, abbiamo dimostrato che mutazioni nella glicoproteina B dell'involucro (gB), che è responsabile dell'entrata virale e della fusione cellulare, potrebbero sorgere durante la produzione del vettore virale. A livello elettrofisiologico, abbiamo inoltre visto che la gB mutata può aumentare la frequenza di potenziali d’azione e contemporaneamente ridurre sia la resistenza di ingresso che il potenziale di riposo neuroni trasdotti. Complessivamente, questi dati suggeriscono che un'attenta valutazione delle glicoproteine dell'involucro è necessaria per sviluppare vettori sicuri non replicativi basati su HSV-1 per il trattamento dei disturbi del SNC. Abbiamo quindi deciso di passare ai vettori Lentivirali (LV), una piattaforma più robusta e caratterizzata nonostante una capacità di carico più limitata rispetto ai vettori HSV. Per potenziare l'effetto protettivo di NPY, abbiamo sviluppato un approccio combinatorio di terapia genica basato sull'espressione di NPY insieme al suo recettore (Y2). Poiché i recettori Y2 agiscono principalmente a livello pre-sinaptico per diminuire il rilascio di glutammato riducendo l’ingresso di Ca2+, l'espressione dei transgeni è stata guidata dal promotore minimal CamKII, orientando così la loro espressione selettivamente nei neuroni eccitatori. Abbiamo successivamente caratterizzato la capacità dei nostri vettori LV di esprimere NPY e il suo recettore funzionale Y2 nei neuroni ippocampali e nel cervello dei topi. In seguito, abbiamo utilizzato un sistema di monitoraggio video-EEG mediante telemetria per valutare l'effetto dei geni terapeutici sul fenotipo epilettico in un modello genetico di epilessia. Abbiamo scoperto che l'espressione combinata di NPY e Y2 è sufficiente a ridurre sia la frequenza che la durata delle crisi nel modello di epilessia Synapsin triple-KO. Questi dati rafforzano ulteriormente l'ipotesi che le strategie mirate all’utilizzo di NPY e Y2 possono avere successo per il trattamento dell'epilessia, in particolare per le forme resistenti ai farmaci ma anche per forme genetiche della malattia.
Ravache, Thaís Terpins, Renata Simões i Marcelo Demarchi Goissis. "Geração de animais transgênicos por inoculação de vetor viral em meio de cultura de óvulos". reponame:Repositório Institucional da UFABC, 2014.
Znajdź pełny tekst źródłaDissertação (mestrado) - Universidade Federal do ABC, Programa de Pós-Graduação em Biotecnociência, 2014.
Desde o século XV, animais fazem parte da rotina na área da pesquisa, principalmente para estudos de doenças, e hoje em dia o modelo animal mais utilizado para estes estudos é o camundongo, tendo uma participação em mais de 90% das pesquisas em todo o mundo, sendo considerado como uma primeira via para definir funções de genes em mamíferos. Os camundongos são considerados os principais modelos nas técnicas de transgenia animal, porém estas técnicas ainda estão em desenvolvimento, uma vez que as metodologias hoje utilizadas para a geração de animais transgênicos ainda se encontram com uma taxa de sucesso considerada baixa e são dispendiosas, necessitando de muitas etapas. Uma das dificuldades é o contato com a membrana do óvulo devido a zona pelúcida, que é considerada uma barreira física. Vetores virais estão em evidência nas técnicas de transgenia animal, sendo o lentivírus o mais utilizado. Portanto, o objetivo deste projeto é estabelecer um protocolo para a integração de DNA exógeno em óvulos por infecção lentiviral, anteriormente a fertilização in vitro juntamente com a técnica de dissecção parcial da zona pelúcida. Como vetor foi utilizado um lentivírus com GFP em sua construção. Para ocorrer a fertilização in vitro, foram feitas coletas de óvulos em camundongos fêmeas da linhagem C57BL/6, tratadas com injeções hormonais, e coletas de espermatozoides em machos desta mesma linhagem. Os óvulos obtidos foram divididos em grupos controle e com dissecção parcial da zona pelúcida, e estes foram subdivididos em grupos com e sem infecção lentiviral. Entre os grupos houve variação de 20% a 56,25% de embriões em estágio de duas células, e em alguns grupos foi possível alcançar o estágio de blastocisto eclodido. Porém não foi possível visualizar a emissão de fluorescência para confirmar a infecção lentiviral. Em conclusão as metodologias utilizadas tanto para a fertilização in vitro como para a dissecção parcial da zona pelúcida foram de sucesso. Porém a integração do DNA exógeno mostrou resultados não conclusivos, necessitando de estudos futuros.
Since the XV century, animals are used routinely in research, mainly for diseases studies, and nowadays the most used animal model is the mouse, which one has more than 90% of participation in researches around the world and it is considered the first track to define gene function in mammals. Mouse is the main model in transgenic techniques, however the methods available to generate transgenic animals still have a considerable low rate, and also it is expensive, requiring many degrees. An ordinary issue is the contact with the membrane of oocyte due zona pellucida that is considered a physical barrier. In transgenic animals technique, it is in evidence the utilization of viral vectors, and the most used are the lentiviruses. Therefore, the objective of this project is to establish a protocol for the integration of exogenous DNA by lentiviral infection into oocytes, before the in vitro fertilization, using the technique of partial dissection of the zona pellucida. It was used as a vector a lentivirus with GFP in your construction. For in vitro fertilization, were collected oocytes from C57Bl/6 mice, treated with hormones, and sperm from males of the same strain. The obtained oocytes were divided in control group and partial dissection of the zona pellucida group, and then subdivided in groups with and without lentiviral infection. Between the groups, was achieved 20% to 56,25% of two cells stage embryo, and hatched blastocysts stage were obtained at some groups. Therefore it was not possible to visualize florescence emission to confirm the lentiviral infection. In conclusion we have a practicable protocol for in vitro fertilization and partial dissection of the zona pellucida, reaching blastocysts stages in two groups. However the integration of exogenous DNA results were inconclusive, requiring further studies.
Molina, Gil Alberto. "Lentiviral vector packaging cell line development using genome editing to target optimal loci discovered by high throughput DNA barcoding". Thesis, University College London (University of London), 2017. http://discovery.ucl.ac.uk/1573558/.
Pełny tekst źródłaChang, Chia-Wei. "Polycistronic lentiviral vector for hit and run reprogramming of mouse and human somatic cells to induced pluripotent stem cell". Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2009. https://www.mhsl.uab.edu/dt/2009p/changc.pdf.
Pełny tekst źródłaDarbey, Annalucia Leigh. "Targeting and repair of adult testicular somatic cells through viral gene therapy". Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/33252.
Pełny tekst źródłaSTARINIERI, FRANCESCO. "Investigating liver tissue dynamics to improve in vivo gene therapy". Doctoral thesis, Università Vita-Salute San Raffaele, 2022. http://hdl.handle.net/20.500.11768/122896.
Pełny tekst źródłaIl fegato è un importante organo bersaglio per la terapia genica in vivo, a causa del suo ruolo in diversi disordini della coagulazione e malattie metaboliche. I vettori adeno-associati (AAV) sono stati ampiamente usati per la terapia genica diretta al fegato, ottenendo significativi risultati terapeutici in diversi trial clinici. Nonostante il genoma dei vettori AAV rimane prevalentemente episomale, il transgene è mantenuto per diversi anni nel fegato adulto. Tuttavia, la proliferazione degli epatociti durante la crescita ostcola l’utilizzo dei vettori AAV in individui giovani. In passato abbiamo sviluppato vettori lentivirali (LV) che integrano il loro genoma in quello della cellula, e hanno mostrato espressione stabile in topi, cani e primati non umani adulti. Abbiamo effettuato un’analisi approfondita del mantenimento degli epatociti trasdotti con LV in seguito a crescita post-natale e omeostasi, e dell’impatto dell’età sulla terapiagenica con LV diretta al fegato nel topo. Abbiamo osservato una maggiore proliferazione degli epatociti in topi neonati, che decresce nel tempo fino, con solo il 25% degli epatociti che contribuisce alla crescita, generando la grande maggioranza del fegato adulto. Non abbiamo osservato differenze rilevanti tra la proliferazione di epatociti trasdotti e non trasdotti. Abbiamo poi osservato una maggiore efficienza di trasduzione degli epatociti in topi neonati o giovani rispetto agli adulti, in parallelo a un minor indirizzamento nelle cellule non parenchimali. Somministrando intravena (i.v.) un LV che esprime il fattore IX della coaglazione (FIX) umano abbiamo osservato la maggior produzione di FIX in topi trattai da giovani, che decresce sostanzialmente in quelli trattati dalla 4° settimana di vita. I topi neonati hanno mostrato invece un livello intermedio. I topi giovani hanno mostrato inoltre una percentuale più alta di epatociti trasdotti a multipla copia, che può contribuire alla differenza di secrezione. Abbiamo poi esaminato la distribuzione degli epatociti trasdotti nel lobulo epatico e abbiamo una preferenza di trasduzione per gli epatociti nell’area peri-centrale nei topi giovani e in quella peri-portale nei topi adulti. Queste differenze sono mantenute nel tempo, indicando che sono dovute a differenze di trasduzione e non causate da silenziamento del transgene. Abbiamo osservato che anche le cellule di Kupffer si spostano dalla zona centrale a quella portale durante la crescita, ma la loro deplezione aumenta la trasduzione della zona portale nei topi adulti, suggerendo che non determinano la distribuzine del LV nel lobulo. In conclusione, il nostro lavoro mostra che la somministrazione i.v. di LV in topi giovani porta a una maggiore trasduzione degli epatociti e secrezione del prodotto del transgene rispetto ai topi adulti, con mantenimento del transgene in seguito a proliferazione cellulare durante la crescita del fegato. Queste osservazioni forniscono informazioni sullo sviluppo della terapia genica con LV diretta al fegato verso l’applicazione in pazienti pediatrici, e gettano luce sui meccanismi di crescita post-natale del fegato nei topi, che sono rilevanti anche per strategie di modificazione sito-specifica del genoma.
Hiraragi, Hajime. "Study of lentiviral vector for in utero gene transfer and functional analysis of human T-lymphotropic virus type p13(II)". Connect to resource, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1116532636.
Pełny tekst źródłaTitle from first page of PDF file. Document formatted into pages; contains xvii, 230 p.; also includes graphics. Includes bibliographical references (p. 200-230). Available online via OhioLINK's ETD Center
Holder, Maxine Virginia. "Development of a lentiviral vector system based on equine infectious anaemia virus for use in liver directed fetal gene therapy". Thesis, Imperial College London, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.428014.
Pełny tekst źródłaMoussa, Maha. "Immunité et protection induites par un lentivecteur ADN innovant chez les modèles animaux de vaccination VIH-1". Thesis, Université Grenoble Alpes (ComUE), 2015. http://www.theses.fr/2015GREAV029/document.
Pełny tekst źródłaWe recently developed an innovative prototype non-integrative lentivector DNA vaccine against HIV-1 /AIDS that we tested in pilot studies using animal models of HIV vaccine. We found that a single immunization with our prototype vaccine (CAL-SHIV-IN-) allowed the implementation of potent humoral and cellular responses in all immunized macaques. In addition, both types of responses persisted over a period of 74 weeks post-immunization in absence of antigenic boost. The characterization of the above revealed that vaccine specific T cell responses included polyfunctional CD4+ and CD8+ T cells against all antigens expressed by the vaccine. Detailed phenotypic and functional examinations of these cells showed that they were composed of effector (EM) and central memory (CM) T cells. More importantly they also contained a fraction of precursor memory T cells with high proliferative capacity (PHPC). Immune responses primed by our vaccine regiment correlated with protection in all vaccinated macaques (6/6). As expected our vaccine-induced immune responses did not prevent from infection acquisition but controlled the replication of the highly pathogenic and heterologous SIVmac251 challenge given as repeated low dose by the intrarectal mucosal route. All vaccinated animals (6/6) controlled their viremia to undetectable level using conventional PCR during at least 10 months post infection (end of the experiment). We further focused on PHPC responses associated with viral control and found that these cells vigorously proliferate upon ex vivo stimulation with specific antigens in presence of the homeostatic IL-7 and IL-15 cytokines. Proliferating antigen specific cells contained a type of stem cell-like memory T cells (TSCM). These latter (TSCM) might be a major asset in favor of our lentivector and vaccination strategy due to their high capacity for self-regeneration/maintenance in absence of antigen source
Kitowski, Katherine Anne. "A LENTIVIRAL VECTOR CONFERRING COREGULATED, ERYTHROID-SPECIFIC EXPRESSION OF γ-GLOBIN AND shRNA SEQUENCES TO BCL11A FOR THE TREATMENT OF SICKLE CELL DISEASE". OpenSIUC, 2016. https://opensiuc.lib.siu.edu/theses/1995.
Pełny tekst źródłaEstève, Julie. "Transfert de gènes dans les cellules souches pluripotentes induites : application à la thérapie génique de l'hyperoxalurie primitive de type 1". Thesis, Bordeaux, 2018. http://www.theses.fr/2018BORD0280/document.
Pełny tekst źródłaPrimary hyperoxaluria type 1 (or PH1) is an inherited metabolic disorder related to the deficiency of the hepatic AGT enzyme (alanine:glyoxylate aminotransferase), which is encoded by the AGXT gene. In PH1 patients, this deficiency leads to oxalate overexcretion by liver, followed by urine filtration and complexation with calcium to form massive calcium-oxalate nephrolithiasis potentially leading to chronic renal failure. The only available curative treatment is combined hepatorenal allogeneic engraftment, which is currently limited by the availability of transplant donors, significant morbidity and mortality, and the need for long-term immunosuppressive treatment. The aim of our research project is to develop gene therapy for PH1, consisting in engraftment of genetically corrected autologous liver cells. Considering that adult hepatocytes are hardly available and expandable in vitro, we chose to explore the use of induced pluripotent stem cells (iPSCs) to produce human liver cells for application in regenerative medicine. We derived and characterized iPSC lines from PH1 patient fibroblasts after transient expression of reprogramming factors delivered by Sendai virus vectors. We developed two additive gene therapy strategies by inserting a minigene encoding an optimized AGXT cDNA sequence using (1) a lentiviral vector designed for liver-specific expression and (2) homologous recombination process at the AAVS1 locus favoured by the targeted DNA cutting system “CRISPR/Cas9”. Finally, we highlighted therapeutic cassette expression after hepatic differentiation of genetically corrected iPSCs. These results pave the way for regenerative medicine for PH1 by transplantation of genetically modified autologous hepatocyte-like cells derived from patient-specific iPSCs
Lin, Yuan. "In Vivo Imaging of Engraftment and Enrichment of Lentiviral Transduced Hematopoietic Bone Marrow Cells Under MGMT-P140K Mediated Selection". Case Western Reserve University School of Graduate Studies / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=case1295039430.
Pełny tekst źródłaCABRIOLU, ANNALISA. "Sviluppo di vettori virali per la terapia genica della β−Talassemia". Doctoral thesis, Università degli Studi di Cagliari, 2012. http://hdl.handle.net/11584/266135.
Pełny tekst źródłaFacchinello, Nicola. "Conditional inactivation of Emilin1 and Col6a1 genes". Doctoral thesis, Università degli studi di Padova, 2010. http://hdl.handle.net/11577/3422723.
Pełny tekst źródłaTecniche che prevedono il controllo dell’espressione genica tramite inattivazione condizionale sono di particolare utilità nello studio della funzione di geni durante lo sviluppo e nel determinare patologie. In questo lavoro sono stati utilizzati un sistema di silenziamento in vivo del gene Col6a1 mediante RNAi utlizzando vettori lentivirali e un sistema “Cre/loxP” per generare un modello murino di knockout condizionale inducibile. L’uso di vettori lentivirali può accelerare la generazione di animali transgenici con una consistente riduzione dell’espressione genica e in modo inducibile, anche se in letteratura alla tecnica sono state attribuite alcune limitazioni dovute alla bassa efficienza di transgenesi e alla presenza di mosaicismo nei topi così ottenuti. In questo lavoro abbiamo prodotto diverse linee di animali transgenici con diminuiti livelli di messaggero per il gene Col6a1 grazie alla produzione di siRNA. La caratterizzazione delle varie linee e la comparazione del fenotipo con quello dei topi knockout per lo stesso gene ha permesso l’identificazione dei diversi fattori che sono in grado di influire sul processo di silenziamento di Col6a1, un gene codificante per una proteina della matrice extracellulare con un complesso pattern di espressione tessuto specifica. I risultati ottenuti con i vettori pLVTHM e pLVPT-rtTRKRAB, hanno permesso di definire tre importanti fattori come maggiori determinanti nell’efficienza dell’interferenza: la scelta della sequenza interferente, il numero di copie provirali integrate nel genoma e il sito di integrazione degli stessi. É stato inoltre utilizzato un vettore lentivirale (pLVPT-rtTRKRAB) per la produzione inducibile di shRNA mediante somministrazione di doxyciclina. Il controllo dell’espressione dopo doxycicilina è risultato essere stringente in molti tessuti, anche se in alcuni la inattivazione della produzione di shRNA non è stata completa. I risultati ottenuti dimostrano l’applicabilità di vettori lentivirali nella generazione di animali transgenici (Frka, Facchinello, et al., 2009). Emilina1 è una proteina della matrice extracellulare presente nei tessuti connettivi interstiziali e nel sistema cardiovascolare a partire da stadi precoci di sviluppo embrionale e nell’adulto. I topi mancanti di Emilina1 sono ipertesi e mostrano un diametro ridotto dei vasi. Emilina1 svolge la sua funzione regolando la biodisponibilità di TGF-β, una citochina che svolge importanti funzioni nel sistema cardiovascolare. In particolare, è stato dimostrato che Emilina1 inibisce la proteolisi del precursore pro-TGF-β a LAP/TGF-β, un complesso dal quale il fattore di crescita attivo deve essere successivamente rilasciato per permetterne il legame con il recettore. In assenza di Emilina1, la quantità di TGF-β attivo è aumentata, riducendo la proliferazione delle cellule muscolari lisce e quindi il diametro del vaso. Per stabilire se il fenotipo dei topi Emilina1-/- è il risultato di un’alterata morfogenesi dei vasi o se la funzione della proteina è richiesta nella regolazione della pressione e nella struttura del vaso anche nell’animale adulto, è stato necessario produrre un knockout condizionale del gene di Emilin1 in modo da indurre l’assenza della proteina con un preciso controllo temporale e spaziale. Il modello murino prevede la presenza di siti loxP posti nel gene di Emilin1 in modo da produrre l’inattivazione genica, una Cre-ERT2 (cioè una Cre ricombinasi inducibile tramite tamoxifen) e il locus Rosa26R-lacZ (un gene reporter inducibile per la rilevazione istologica delle cellule nelle quali si è avuto il riarrangiamento genetico). É stato preparato un costrutto dove l’esone 1 e 2 del gene di Emilina1 sono fiancheggiati da due siti loxP. Mediante Southern Blot e PCR, è stata verificata la corretta integrazione del costrutto nelle cellule embrionali staminali di topo. 4 cloni ricombinanti omologhi così identificati sono stati trasferiti in vivo mediante microiniezione in blastocisti ottenendo topi chimerici con un grado di chimerismo compreso tra il 10 e il 100%. L’espressione del gene Cre-ERT2 è stato posto sotto il controllo delle sequenze promotoriali proprie di Emilina1 o, alternativamente, del gene per la catena pesante della miosina di muscolo liscio, in modo da essere attivamente espressa dalle cellule che producono Emilina1 o da quelle muscolari lisce rispettivamente. Dopo la somministrazione di tamoxifen, l’attività di entrambi i promotori è evidente sia nelle cellule muscolare lisce vascolari e viscerali, dove SMMHC-CreERT2 induce una ricombinazione più efficiente rispetto al costrutto Emilina1-CreERT2. Le analisi mediante PCR e RT-PCR confermano che la cre ricombinasi sotto il promotore della miosina di muscolo liscio induce efficientemente la ricombinazione dei siti loxP nel locus di Emilina1, permettendo in questo modo una riduzione consistente dei livelli di messaggero. I topi Emilina1flox/flox generati sono fertili e presentano un fenotipo normale e inoltre comparati con degli animali di controllo non mostrano differenze per quanto riguarda l’espressione del messaggero di Emilina1 e nei livelli di pressione sanguigna, confermando che l’introduzione dei siti loxP non interferisce con la regolazione dell’espressione del gene. Risultati preliminari inoltre indicano un aumento della pressione sanguigna nelle doppie linee transgeniche Emilina1flox/flox e SMMHC-Cre-ERT2 in seguito a trattamento con tamoxifen. Questo risultato suggerisce che l’ipertensione non è dovuta ad un’alterata morfogenesi dei vasi sanguigni, ma al ruolo continuativo di Emilina-1 nella regolazione della pressione sanguigna anche nell’adulto.
Ngom, Mor. "Small molecule stimulators for enhanced yield of human hematopoietic stem cells". Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCC320.
Pełny tekst źródłaEfficient lentiviral gene transfer to hematopoietic stem cells is a prerequisite for theultimate goal of gene therapy for a range of major genetic diseases such as β‐thalassemia, Adrenoleucodystrophy and severe combined immnodeficiency. The small molecule UM171 was recently described as having potent ability to stimulate ex vivo expansion of human hematopoietic stem cells, another key to safer and wider application of stem cell mediated therapies. Here we have conducted additional studies to confirm the stem cell expansion properties of UM171 and in the course of this work discovered that it also has the ability to significantly enhance the efficiency of the lentiviral transduction of primitive hematopietic cells in human cord blood. Subsequent work confirmed that this enhancing effect extends importantly to the most primitive hematopoietic subset as assessed phenotypically and by functional readout in immunodeficient mouse xenografts. Further detailed characterization ofthis phenomenom revealed that UM171’s effects are manifest rapidly and extend to a range of lentiviral pseudotypes. Together these findingsprovide an avenue for improved protocols for hematopoietic stem cell transduction that achieve higher gene efficiency and stem cell recovery coupled with the potential for reduced viral titer requirements
Gagnepain, Anaïs. "Évaluation de nouveaux pseudotypes de vecteurs lentiviraux pour le transfert de gènes dans les cellules hématopoiétiques". Thesis, Lyon, École normale supérieure, 2014. http://www.theses.fr/2014ENSL0939/document.
Pełny tekst źródłaLentiviral vectors and their ability to transfer gene into hematopoietic stem cells are currently evaluated for the cure of several single-gene diseases (eg : B-thalassemia, Adrenoleucodystrophy, SCID). Likewise, gene transfer into B and T lymphocytes is of major interest in gene therapy and immunotherapy. We engineered new lentiviral vectors pseudotyped by some chimeric (BaEV/TR) and mutant (BaEVRLess) glycoproteins from the baboon endogenous retrovirus. We demonstrated that these new vectors can transduce more efficiently resting and mild stimulated hematopoietic stem cells than obtained with lentivectors pseudotyped by the glycoprotein G from the vesicular stomatitis virus (VSV-G). It is the same with the recently developed lentiviral vectors pseudotyped by the H and F glycoprotein from measles virus (H/F-LVs). We also compared the ability of the H/F-LVs with the BaEV/TR and BaEVRLess lentiviral vector pseudotype to transfer genes into B and T lymphocytes and into the whole T lineage. From now on, we are able to propose adapted vectors for gene transfer at each stage of differentiation from CD34+ cells to thymocytes and mature T cells. This could allow us to propose some new clinical protocols in gene therapy with a co-transplantation of genetically modified stem cells and their differentiated T progenitors in order to reduce the aplasia stage induced by current transplantation protocols
Vogiatzis, Stefania. "Generation of lentiviral vectors expressing chimeric NEDD4 ubiquitin ligases specifically targeting alpha-synuclein: a tool for studying Parkinson's disease pathogenesis and for the development of innovative therapeutic approaches". Doctoral thesis, Università degli studi di Padova, 2019. http://hdl.handle.net/11577/3424860.
Pełny tekst źródłaANNONI, ANDREA. "Strategies for tolerance induction to gene therapy derived products". Doctoral thesis, Università degli Studi di Roma "Tor Vergata", 2009. http://hdl.handle.net/2108/763.
Pełny tekst źródłaDue to their ability to transduce non-dividing cells and stably integrate, lentiviral vectors (LV) are a candidate system for therapeutic gene transfer in a number of genetic diseases. However, the use of LV may be hampered by their ability to trigger innate and adaptive immunity. Immune responses against genetically modified cells represent a major obstacle to the success of gene therapy. Cellular and humoral immune responses to vector associated and transgene-derived proteins lead to prompt elimination of transgene expressing cells abrogating, the benefits of gene transfer. A non-therapeutic murine model of gene therapy has been established. LV, encoding for green fluorescent protein (GFP) under the control of an ubiquitous promoter, was intravenously administrated into immunocompetent mice in order to define the kinetics of transgene expression, characterize the anti-transgene immune response and develop different approaches to overcome the anti-transgene immunity and achieve long term transgene expression. Several strategies have been used to limit immune response following gene transfer, including immunosuppression, and the use of less immunogenic routes of administration. In the present work we focused our attention in inducing immunological tolerance to transgene expressing cells as first approach, by a cellular therapy, and second, through the use micro-RNA (mir) regulated lentiviral vectors. Regulatory T cells (Tregs), which have been demonstrated to control immune responses in vivo, were tested for their ability to suppress anti-transgene response leading to stable long-term gene expression. Adoptive transfer of naturally occurring CD4+CD25+ Tregs (nTregs) isolated from wt mice or from transgene tolerant transgenic (tg) mice did not suppress the anti-transgene immune response after LV delivery. These data demonstrate that neither increasing the endogenous pool of nTregs nor transferring nTregs selected in a transgene expressing thymus can modulate the immune response and mediate sustained transgene expression. Conversely, adoptive transfer of antigen presenting cells (APC) isolated from transgene tolerant tg mice efficiently reduced the immune response leading to stable LV-encoded protein expression in vivo. Most of the immunogenicity of the LV-based gene transfer protocols depends on the transduction and transgene expression by professional APC that prime T cells inducing an anti-transgene immune response. The use of tissue specific promoters, such as the albumin promoter, has been explored in order to target transgene expression in hepatocytes and drastically reduce transgene expression in APC. Recently, in the same direction, Brown et al. (Nat. Med. 2006; 12:585-591) demonstrated that addition of target sequences for an hematopoietic-specific micro-RNA, mir-142-3p, into LV encoding for GFP under transcriptional control of the ubiquitous PGK promoter (LV.PGK.GFP.142-3pT) prevented transgene expression in all hematopoietic lineages and led to stable transgene expression in the liver. Here, we set out to elucidate the immunological events that enabled stable gene transfer with this microRNA-regulated LV. Results demonstrate that systemic gene transfer by the mir-142-regulated LV can provide robust tolerance to a specific antigen which is mediated by CD4+ Tregs. These findings will have important implications for developing future gene therapy strategies.
PASINI, SILVIA. "Role of activated transcription factor 4 (ATF4) in learning and memory". Doctoral thesis, Università degli Studi di Milano-Bicocca, 2011. http://hdl.handle.net/10281/27132.
Pełny tekst źródłaZanatta, Daniela Bertolini. "Sequenciamento de um código de barras como ferramenta para quantificação de alterações na dinâmica de populações celulares transduzidas com vetores lentivirais". Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/87/87131/tde-21092012-102415/.
Pełny tekst źródłaRetroviral vectors represent one of the best options for gene transfer and therapy, where long-term transgene expression is required. However, insertion of the provirus can cause insertional mutagenesis, which may have adverse consequences, such as induction of proto-oncogenes. Such events have been described in clinical trials for the treatment of SCID-X1, chronic granulomatous disease and beta thalessemia with some retroviral vectors. Currently, there are few simple and quick methods that can reveal and quantify clonal expansion. Thus, we describe the construction of a vector library containing random markers, called \"barcodes\". The sequencing of the barcode could reveal, characterize and quantify the clonal expansion of a transduced cells population. This methodology will be valuable to test new arrangements of promoters and therapeutic genes, allowing the development of safer vectors, helping to reduce the probability of clonal proliferation events triggered by insertional mutagenesis.
Knight, S. B. "Lentiviral vectors for gene therapy". Thesis, University College London (University of London), 2012. http://discovery.ucl.ac.uk/1346459/.
Pełny tekst źródłaWard, N. J. "Lentiviral vectors for treatment of haemophilia". Thesis, University College London (University of London), 2010. http://discovery.ucl.ac.uk/19905/.
Pełny tekst źródłaReis, Luiza Cunha Junqueira. "Geração de células de pluripotência induzida (iPS) humanas utilizando vetores lentivirais e determinação do perfil de integração lentiviral". Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/60/60135/tde-26022013-092913/.
Pełny tekst źródłaThe induced pluripotent stem (iPS) cells came with the promise of circumvent some of the limitations in the use of embryonic stem cells, like ethical issues, biological safety, immune compatibility and availability. This cells can be generated from somatic cells of normal individuals or from patients with some genetic disease, making then an important tool for drug screening, construction of disease models and toxicological trials. Great advances have happened in reprogramming differentiated cells through the forced exogenous expression of transcription factors (TF), mostly by lentiviral vectors (LV), which provide an efficient reprogramming. However, the lentiviral insertion in the human genome and its influence in reprogramming is not well known. In this work, we evaluate the insertion profile of LV used to generate human iPS cells. The iPS cells were generated, by our group, from human fibroblasts transduced by LV containing 3 TF [SOX2, TCL-1A and C-MYC (TSM reprogrammed cell)], and from mesenchymal cells derived from human adipose tissue transduced by a polycistronic LV containing 4 TF [OCT4, SOX2, KLF4 and C-MYC (iPS 4TF)]. Five isolated colonies of each iPS cell were mapped and analyzed for the insertion sites through LM-PCR technique. The digested genomic DNA was amplified with a primer for the viral LTR e another for a synthetic linker. The products were cloned, sequenced and analyzed in database to identify similarities with the human genome, among other analyzes. In TSM cell, 176 sequences, derived from the LM-PCR technique, presented identity with the human genome, and about 50% of those occurred in genic regions with 94% in introns. In iPS 4TF, 251 sequences showed identity, with about 45% reaching genes, 92% of these in introns. The insertions were distributed on all chromosomes, with preference for the 16, 17 and 20 for the TSM cell, and for the 11, 15 and 17 for the iPS 4TF. We analyzed the distance of the insertion from de transcription start site, and insertions near CpG islands, which, overall, correspond to regulatory regions. The highest proportion of insertion occurred starting ±30Kb distance from these sites. The fragile sites and the repetitive regions of the genome were also reached, but with low frequency. The results showed a preference of lentiviral insertion for genic regions in iPS, indicating the potential participation of proteins like LEDGF/p75 in integration in the cells of this work. This work shows that the integration site may contribute to the reprogramming, and, despite possible negative effects of integration, these iPS cells are still an important tool for in vitro studies. Identify factors that influence the selection of insertion site is important for determination of \"safe\" chromosomal regions for the integration, increasing the safe in clinical use.