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1
Choudhury, Sourav Roy. "Developing an Adeno-Associated Viral Vector (AAV) Toolbox for CNS Gene Therapy: A Dissertation." eScholarship@UMMS, 2001. http://escholarship.umassmed.edu/gsbs_diss/809.
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Neurological disorders – disorders of the brain, spine and associated nerves – are a leading contributor to global disease burden with a sizable economic cost. Adeno-associated viral (AAV) vectors have emerged as an effective platform for CNS gene therapy and have shown early promise in clinical trials. These trials involve direct infusion into brain parenchyma, an approach that may be suboptimal for treatment of neurodegenerative disorders, which often involve more than a single structure in the CNS. However, overall neuronal transduction efficiency of vectors derived from naturally occurring AAV capsids after systemic administration is relatively low. We have developed novel capsids AAV-AS and AAV-B1 that lead to widespread gene delivery throughout the brain and spinal cord, particularly to neuronal populations. Both transduce the adult mouse brain >10-fold more efficiently than the clinical gold standard AAV9 upon intravascular infusion, with gene transfer to multiple neuronal sub-populations. These vectors are also capable of neuronal transduction in a normal cat. We have demonstrated the efficacy of AAV-AS in the context of Huntington's disease by knocking down huntingtin mRNA 33-50% after a single intravenous injection, which is better than what can be achieved by AAV9 at the particular dose. AAVB1 additionally transduces muscle, beta cells, pulmonary alveoli and retinal vasculature at high efficiency, and has reduced sensitivity to neutralizing antibodies in human sera. Generation of this vector toolbox represents a major step towards gaining genetic access to the entire CNS, and provides a platform to develop new gene therapies for neurodegenerative disorders.
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Choudhury, Sourav Roy. "Developing an Adeno-Associated Viral Vector (AAV) Toolbox for CNS Gene Therapy: A Dissertation." eScholarship@UMMS, 2016. https://escholarship.umassmed.edu/gsbs_diss/809.
Full textAbstract:
Neurological disorders – disorders of the brain, spine and associated nerves – are a leading contributor to global disease burden with a sizable economic cost. Adeno-associated viral (AAV) vectors have emerged as an effective platform for CNS gene therapy and have shown early promise in clinical trials. These trials involve direct infusion into brain parenchyma, an approach that may be suboptimal for treatment of neurodegenerative disorders, which often involve more than a single structure in the CNS. However, overall neuronal transduction efficiency of vectors derived from naturally occurring AAV capsids after systemic administration is relatively low. We have developed novel capsids AAV-AS and AAV-B1 that lead to widespread gene delivery throughout the brain and spinal cord, particularly to neuronal populations. Both transduce the adult mouse brain >10-fold more efficiently than the clinical gold standard AAV9 upon intravascular infusion, with gene transfer to multiple neuronal sub-populations. These vectors are also capable of neuronal transduction in a normal cat. We have demonstrated the efficacy of AAV-AS in the context of Huntington's disease by knocking down huntingtin mRNA 33-50% after a single intravenous injection, which is better than what can be achieved by AAV9 at the particular dose. AAVB1 additionally transduces muscle, beta cells, pulmonary alveoli and retinal vasculature at high efficiency, and has reduced sensitivity to neutralizing antibodies in human sera. Generation of this vector toolbox represents a major step towards gaining genetic access to the entire CNS, and provides a platform to develop new gene therapies for neurodegenerative disorders.
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Ross, Colin J. D. "Immuno-isolation gene therapy for lysosomal storage disease /." *McMaster only, 2001.
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Heller, Raoul. "Engineering of human artificial mini-chromosomes." Thesis, University of Oxford, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.360317.
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Ahmed, Seemin Seher. "rAAV-Mediated Gene Transfer For Study of Pathological Mechanisms and Therapeutic Intervention in Canavan's Disease: A Dissertation." eScholarship@UMMS, 2014. https://escholarship.umassmed.edu/gsbs_diss/749.
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Canavan’s Disease is a fatal Central Nervous System disorder caused by genetic defects in the enzyme – aspartoacylase and currently has no effective treatment options. We report additional phenotypes in a stringent preclinical aspartoacylase knockout mouse model. Using this model, we developed a gene therapy strategy with intravenous injections of the aspartoacylase gene packaged in recombinant adeno associated viruses (rAAVs). We first investigated the CNS gene transfer abilities of rAAV vectors that can cross the blood-brain-barrier in neonatal and adult mice and subsequently used different rAAV serotypes such as rAAV9, rAAVrh.8 and rAAVrh.10 for gene replacement therapy. A single intravenous injection rescued lethality, extended survival and corrected several disease phenotypes including motor dysfunctions. For the first time we demonstrated the existence of a therapeutic time window in the mouse model. In order to limit off-target effects of viral delivery we employed a synthetic strategy using microRNA mediated posttranscriptional detargeting to restrict rAAV expression in the CNS. We followed up with another approach to limit peripheral tissue distribution. Strikingly, we demonstrate that intracerebroventricular administration of a 50-fold lower vectors dose can rescue lethality and extend survival but not motor functions. We also study the contributions of several peripheral tissues in a primarily CNS disorder and examine several molecular attributes behind pathogenesis of Canavan’s disease using primary neural cell cultures. In summary, this thesis describes the potential of novel rAAV-mediated gene replacement therapy in Canavan’s disease and the use of rAAVs as a tool to tease out its pathological mechanism.
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Ahmed, Seemin Seher. "rAAV-Mediated Gene Transfer For Study of Pathological Mechanisms and Therapeutic Intervention in Canavan's Disease: A Dissertation." eScholarship@UMMS, 2012. http://escholarship.umassmed.edu/gsbs_diss/749.
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Canavan’s Disease is a fatal Central Nervous System disorder caused by genetic defects in the enzyme – aspartoacylase and currently has no effective treatment options. We report additional phenotypes in a stringent preclinical aspartoacylase knockout mouse model. Using this model, we developed a gene therapy strategy with intravenous injections of the aspartoacylase gene packaged in recombinant adeno associated viruses (rAAVs). We first investigated the CNS gene transfer abilities of rAAV vectors that can cross the blood-brain-barrier in neonatal and adult mice and subsequently used different rAAV serotypes such as rAAV9, rAAVrh.8 and rAAVrh.10 for gene replacement therapy. A single intravenous injection rescued lethality, extended survival and corrected several disease phenotypes including motor dysfunctions. For the first time we demonstrated the existence of a therapeutic time window in the mouse model. In order to limit off-target effects of viral delivery we employed a synthetic strategy using microRNA mediated posttranscriptional detargeting to restrict rAAV expression in the CNS. We followed up with another approach to limit peripheral tissue distribution. Strikingly, we demonstrate that intracerebroventricular administration of a 50-fold lower vectors dose can rescue lethality and extend survival but not motor functions. We also study the contributions of several peripheral tissues in a primarily CNS disorder and examine several molecular attributes behind pathogenesis of Canavan’s disease using primary neural cell cultures. In summary, this thesis describes the potential of novel rAAV-mediated gene replacement therapy in Canavan’s disease and the use of rAAVs as a tool to tease out its pathological mechanism.
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Yogalingam, 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.
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Carty, Nikisha Christine. "Recombinant AAV Gene Therapy and Delivery." Scholar Commons, 2009. https://scholarcommons.usf.edu/etd/1890.
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Alzheimer's disease (AD), first characterized in the early 20th century, is a common form of dementia which can occur as a result of genetic mutations in the genes encoding presenilin 1, presenilin 2, or amyloid precursor protein (APP). These genetic alterations can accelerate the pathological characteristics of AD, including the formation of extracellular neuritic plaques composed of amyloid beta peptides and the formation of intracellular neurofibrillary tangles consisting of hyperphosphorylated tau protein. Ultimately, AD results in gross neuron loss in the brain which is evidenced clinically as a progressive decline in mental capacity. A strong body of scientific evidence has previously demonstrated that the driving factor in the pathogenesis of AD is potentially the accumulation of Aß peptides in the brain. Thus, reduction of Aß deposition is a major therapeutic strategy in the treatment of AD. Recently it has been suggested that Aß accumulation in the brain is modulated, not only by Aß production, but also by its degradation. Several important studies have demonstrated that Aß degradation is modulated by several endogenous zinc metalloproteases shown to have amyloid degrading capabilities. These endogenous proteases include neprilysin (NEP), endothelin converting enzyme (ECE), insulin degrading enzyme (IDE) and matrix metalloprotease 9 (MMP9). In this investigation we study the effects of upregulating expression of several of these proteases through administration of recombinant adeno-associated viral vector (rAAV) containing both endogenous and synthetic genes for ECE and NEP on amyloid deposition in amyloid precursor protein (APP) plus presenilin-1 (PS1) transgenic mice. rAAV administration directly into the brain resulted in increased expression of ECE and NEP and a substantial decrease in amyloid pathology. We were able to significantly increase the area of viral distribution by using novel delivery methods resulting in increased gene expression and distribution.
These data support great potential of gene therapy as a method of treatment for neurological diseases. Optimization of gene transfer methods aimed at a particular cell type and brain region in the CNS can be accomplished using AAV serotype specificity and novel delivery techniques leading to successful gene transduction thus providing a promising therapeutic avenue through which to treat AD.
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Limberis, 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.
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"16th September 2002." Accompanying CD contains 2 MPEG clips with accompanying text, and a copy in PDF format of: Recovery of airway cystic fibrosis transmembrane conductance regulator function in mice with cystic fibrosis after single-dose lentivirus-mediated gene transfer / M. Limberis ... [et al.], published in Human gene therapy vol. 13 (2002). Bibliography: leaves xxix-li. This thesis focuses on modulating the physical barriers of the airway epithelium with mild detergents, so as to enhance gene transfer by a HIV-1 based lentivirus vector in vivo. The efficiency of the gene transfer was evaluated in the nasal airway of C57B1/6 mice using the Lac Z marker gene. This demonstration of lentivirus-mediated in vivo recovery of CFTR function in CF airway epithelium illustrated the potential of combining a pre-conditioning of the airway surface with a simple and brief HIV-1 based gene transfer vector exposure to produce therapeutic gene expression in the intact airway.
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Foster, Robert Graham. "Development of a modular in vivo reporter system for CRISPR-mediated genome editing and its therapeutic applications for rare genetic respiratory diseases." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/33040.
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Rare diseases, when considered as a whole, affect up to 7% of the population, which would represent 3.5 million individuals in the United Kingdom alone. However, while 'personalised medicine' is now yielding remarkable results using recent sequencing technologies in terms of diagnosing genetic conditions, we have made much less headway in translating this patient information into therapies and effective treatments. Even with recent calls for greater research into personalised treatments for those affected by a rare disease, progress in this area is still severely lacking, in part due to the astronomical cost and time involved in bringing treatments to the clinic. Gene correction using the recently-described genome editing technology CRISPR/Cas9, which allows precise editing of DNA, offers an exciting new avenue of treatment, if not cure, for rare diseases; up to 80% of which have a genetic component. This system allows the researcher to target any locus in the genome for cleavage with a short guide-RNA, as long as it precedes a highly ubiquitous NGG sequence motif. If a repair sequence is then also provided, such as a wild-type copy of the mutated gene, it can be incorporated by homology-directed repair (HDR), leading to gene correction. As both guide-RNA and repair template are easily generated, whilst the machinery for editing and delivery remain the same, this system could usher in the era of 'personalised medicine' and offer hope to those with rare genetic diseases. However, currently it is difficult to test the efficacy of CRISPR/Cas9 for gene correction, especially in vivo. Therefore, in my PhD I have developed a novel fluorescent reporter system which provides a rapid, visual read-out of both non-homologous end joining (NHEJ) and homology-directed repair (HDR) driven by CRISPR/Cas9. This system is built upon a cassette which is stably and heterozygously integrated into a ubiquitously expressed locus in the mouse genome. This cassette contains a strong hybrid promoter driving expression of membrane-tagged tdTomato, followed by a strong stop sequence, and then membrane-tagged EGFP. Unedited, this system drives strong expression of membrane-tdTomato in all cell types in the embryo and adult mouse. However, following the addition of CRISPR/Cas9 components, and upon cleavage, the tdTomato is rapidly excised, resulting via NHEJ either in cells without fluorescence (due to imperfect deletions) or with membrane-EGFP. If a repair template containing nuclear tagged-EGFP is also supplied, the editing machinery may then use the precise HDR pathway, which results in a rapid transition from membrane-tdTomato to nuclear- EGFP. Thereby this system allows the kinetics of editing to be visualised in real time and allows simple scoring of the proportion of cells which have been edited by NHEJ or corrected by HDR. It therefore provides a simple, fast and scalable manner to optimise reagents and protocols for gene correction by CRISPR/Cas9, especially compared to sequencing approaches, and will prove broadly useful to many researchers in the field. Further to this, I have shown that methods which lead to gene correction in our reporter system are also able to partially repair mutations found in the disease-causing gene, Zmynd10; which is implicated in the respiratory disorder primary ciliary dyskinesia (PCD), for which there is no effective treatment. PCD is an autosomal-recessive rare disorder affecting motile cilia (MIM:244400), which results in impaired mucociliary clearance leading to neonatal respiratory distress and recurrent airway infections, often progressing to lung failure. Clinically, PCD is a chronic airway disease, similar to CF, with progressive deterioration of lung function and lower airway bacterial colonization. However, unlike CF which is monogenic, over 40 genes are known to cause PCD. The high genetic heterogeneity of this rare disease makes it well suited to such a genome editing strategy, which can be tailored for the correction of any mutated locus.
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Keeler, Allison M. "Gene Therapy for Very Long Chain Acyl-coA Dehydrogenase Deficiency Using Adeno-Associated Virus Vectors: A Dissertation." eScholarship@UMMS, 2012. https://escholarship.umassmed.edu/gsbs_diss/632.
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Very long chain acyl-coA dehydrogenase (VLCAD) is the rate-limiting step in mitochondrial fatty acid oxidation. VLCAD deficient mice and patients’ clinical symptoms stem from not only an energy deficiency but also long-chain metabolite accumulations. VLCAD deficient mice were treated systemically with 1x10 12 vector genomes of rAAV9-VLCAD. Expression was detected in the liver, heart and muscle. Also substantial expression of VLCAD was noted in the brain, where it was expressed across different sections of the brain and in different cell types with different morphologies. Biochemical correction was observed in vector-treated mice beginning two weeks post-injection, as characterized by a significant drop in long chain fatty acyl accumulates in whole blood after an overnight fast. Changes persisted through the termination point around 20 weeks post injection. Magnetic resonance spectroscopy (MRS) and tandem mass spectrometry (MS/MS) revealed normalization of intramuscular lipids in treated animals. Correction was not observed in liver tissue extracts, but cardiac muscle extracts showed significant reduction of long chain metabolites. Disease-specific phenotypes were characterized, including thermoregulation and maintenance of euglycemia after a fasting cold challenge. Internal body temperatures of untreated VLCAD-/- mice dropped below 20°C and the mice became lethargic, requiring euthanasia. In contrast all rAAV9-treated VLCAD-/- mice and the wild-type controls maintained body temperatures. rAAV9-treated VLCAD-/- mice maintained euglycemia, whereas untreated VLCAD-/- mice suffered hypoglycemia following a fasting cold challenge. These promising results suggest rAAV9 gene therapy as a potential treatment for VLCAD deficiency in humans.
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Whalen, Michael. "Treating GM1 Gangliosidosis With Ex Vivo Hematopoietic Stem Cell Gene Therapy Without Using Total Body Irradiation: A Masters Thesis." eScholarship@UMMS, 2011. https://escholarship.umassmed.edu/gsbs_diss/558.
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GM1 gangliosidosis is an autosomal recessive lysosomal storage disease, caused by a deficiency in the enzyme β-galactosidase. The disease affects the CNS, liver, kidney, heart and skeletal system, leading to severe neurodegeneration and death. We propose to treat this disorder using ex vivo hematopoietic stem cell therapy. The effectiveness of this therapy requires the recruitment of transduced donor cells to the CNS. This is only found to occur after mice are conditioned with total body irradiation, due to the increase in CNS cytokine production and blood brain barrier permeability that occurs. As the use of total body irradiation in pediatric patients has been linked to future developmental problems, this myeloablation approach is often avoided in younger patients in favor of a conditioning regimen using the chemotherapy drugs, busulfan and cyclophosphamide. Whether donor cells can enter the CNS when a busulfan and cyclophosphamide conditioning regimen is used has not been determined. In this study we plan to quantify the cytokine and blood-brain barrier permeability increases necessary for donor cells to be recruited to the CNS after total body irradiation. We will then investigate whether busulfan and cyclophosphamide conditioning and/or the chronic neuroinflammation present in GM1 mice can produce similar conditions and facilitate the recruitment of donor hematopoietic stem cells to the CNS. Finally we will assess whether ex vivo hematopoietic stem cell gene therapy is still an effective therapy when busulfan and cyclophosphamide are used for myeloablative conditioning.
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Stoica, Lorelei I. "Gene Therapy for Amyotrophic Lateral Sclerosis: An AAV Delivered Artifical MicroRNA Against Human SOD1 Increases Survival and Delays Disease Progression of the SOD1G93A Mouse Model: A Dissertation." eScholarship@UMMS, 2015. http://escholarship.umassmed.edu/gsbs_diss/813.
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of motor neurons, resulting in progressive muscle weakness, atrophy, paralysis and death within five years of diagnosis. About ten percent of cases are inherited, of which twenty percent are due to mutations in the superoxide dismutase 1 (SOD1) gene. Since the only FDA approved ALS drug prolongs survival by just a few months, new therapies for this disease are needed. Experiments in transgenic ALS mouse models have shown that decreasing levels of mutant SOD1 protein alters and in some cases entirely prevents disease progression. We explored this potential therapeutic approach by using a single stranded AAV9 vector encoding an artificial microRNA against human SOD1 injected bilaterally into the cerebral lateral ventricles of neonatal SOD1G93A mice. This therapy extended median survival from 135 to 206 days (a 50% increase) and delayed hind limb paralysis. Animals remained ambulatory until endpoint, as defined by a sharp drop in body weight. Treated animals had a reduction of mutant human SOD1 mRNA levels in upper and lower motor neurons. As compared to untreated SOD1G93A mice, the AAV9 treated mice also had significant improvements in multiple parameters including the number of motor neurons, diameter of ventral root axons, and degree of neuroinflammation in the spinal cord. These studies clearly show that an AAV9-delivered artificial microRNA is a translatable therapeutic approach for ALS.
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Zeiler, Kristin. "Chosen Children? : An empirical study and a philosophical analysis of moral aspects of pre-implantation genetic diagnosis and germ-line gene therapy." Doctoral thesis, Linköpings universitet, Hälsa och samhälle, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-4276.
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With pre-implantation genetic diagnosis (PGD), genetic testing and selective transfer of embryos is possible. In the future, germ-line gene therapy (GLGT) applied to embryos before implantation, in order to introduce missing genes or replace mutant ones, may be possible. The objective of this dissertation is to analyse moral aspects of these technologies, as described by eighteen British, Italian and Swedish gynaecologists and geneticists. The objective is systematised into three parts: research interviews and qualitative analysis, philosophical analysis, and elaboration of a framework that supports the combination of analytic methods. PGD was described as positive since it enabled some couples at risk for a genetic disease to have a child without the disease. PGD was described as in different senses ‘better’ than methods for prenatal diagnosis and selective termination of pregnancy. It was also described as positive since it provided couples at risk with one more option, even if it did not result in the birth of a healthy child. However, interviewees were concerned about the difficulty of defining and evaluating genetic disease. They were also concerned about patients’ choices, and about exaggerated use or misuse. Whereas PGD gave rise to ambivalence in terms of how to understand, describe and evaluate it, GLGT was often described as unrealistic or undesirable. The results of the qualitative analysis are used in a philosophical analysis of the concepts of choice, autonomous choice, ambivalence, trust and ambivalence in trust relations. A set of distinct characteristics of each concept are elaborated. The results of the philosophical analysis are used in the discussion of the results of the qualitative analysis. The study shows that the technologies imply both ‘new’ ways to perform ‘old’ medical practices and ‘new’ practices. Old moral questions are reformulated. New moral questions are added. Against the background of this, the concept of genetic identity is discussed. Key words: empirical ethics, pre-implantation genetic diagnosis, germ-line gene therapy, qualitative research, philosophical analysis, medical progress, genetic disease, choice, autonomous choice, ambivalence, trust, genetic identity.
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Mola, Caminal Marina. "Genetic contribution to functional outcome and disability after stroke = Contribució genètica al pronòstic funcional i la discapacitat després d'un ictus." Doctoral thesis, Universitat de Barcelona, 2017. http://hdl.handle.net/10803/406139.
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Cerebrovascular disease is the leading cause of disability in adults. Independent of clinical variables such as infarct size and location, stroke subtype, and vascular risk factors, individuals have disparate responses during the recovery process after a stroke is diagnosed. This degree of response is known to be influenced by many factors. Different metabolic pathways are involved in the cerebral ischemic damage response and their activity may be modulated by variation in the genes encoding their components. Thus, the aim of this thesis was to identify the genetic and epigenetic components underlying the recovery process after ischemic stroke in order to in a near future improve the prognosis and reduce the disability rates by personalizing the rehabilitation strategies.
Studying the genetic component of a complex disease is still a challenging task for scientists. Complex traits depend largely on the individual’s environment and lifestyle, and also on multiple genetic variants with small effects. The interplay between genetic and environmental factors is the key to understand the pathophysiology of such diseases. Ischemic stroke outcome is conditioned by the effect of multiple clinical parameters. For this reason, the first step of this project was to define and establish extremely restrictive selection criteria to obtain a highly homogeneous cohort. Patients were selected with functional independence previous to an anterior territory stroke. Exclusion criteria included patients with minor and lacunar strokes, among other constraints. Therefore, to carry out this project it was imperative to request collaboration from International Consortia in order to overcome the major limiting factor, the sample size.
To elucidate the genomic contribution to ischemic stroke outcome, the present thesis used 4 different techniques based on the latest technologic advances. First, a meta-analysis of genome-wide association studies (GWAS) to detect common single nucleotide variants (SNPs) associated with functional status at 3 months post-stroke (the variants most strongly related to functional outcome were selected for replication in an independent set of individuals). Second, as a complementary technique, an exome sequencing study (WES) comparing two groups of ischemic stroke cases with poor or favorable outcome, was used to identify rare genetic variants. The third approach was an epigenome-wide association study (EWAS) to evaluate the influence of acute phase DNA methylation status on functional outcome. The fourth technique utilized a gene expression analysis with candidate regions previously identified. Measures of outcome at 3 months were rated according to modified Rankin Scale (mRS) by trained neurologists.
As a result of this research, a novel locus in PATJ gene was identified as strongly associated with functional outcome after stroke. The EWAS also identified three methylation loci which were statistically significant, where the most striking occurrence was found on the TRPV1 gene. The results presented in this thesis demonstrates the first findings supported with a meta-analysis at genome-wide level of the genetic contribution to mid-term stroke prognosis, as well as the first epigenome-wide association study on ischemic stroke functional outcome.L’accident cerebrovascular és la principal causa de discapacitat en adults. Existeix una gran variabilitat en el grau de recuperació entre els individus que han patit un ictus, independentment de la grandària de l’infart, subtipus d’ictus i factors de risc vascular. Aquesta variabilitat pot estar causada per diversos factors. Diferents vies metabòliques implicades en la resposta al dany isquèmic cerebral es poden veure afectades per variació en els gens que codifiquen els seus components. Per això, l’objectiu d’aquesta tesi va ser identificar el component genètic i epigenètic subjacent al procés de recuperació d’un ictus, per en un futur poder millorar-ne el pronòstic i reduir la taxa de discapacitat personalitzant les estratègies de rehabilitació. Estudiar la genètica d’una malaltia complexa és encara avui un repte per la ciència, ja que aquestes depenen en gran mesura de l’estil de vida i els factors ambientals, així com de múltiples variants genètiques amb petits efectes. Per tant, la interacció entre la càrrega genètica i l’ambient és la clau per entendre la fisiopatologia d’aquestes malalties. El pronòstic de l’ictus es veu afectat per l’efecte de nombrosos paràmetres clínics. Per aquest motiu, el primer pas de l’estudi va ser establir uns criteris d’inclusió altament restrictius per tal d’obtenir una cohort d’ictus isquèmics el màxim d’homogènia. Només van ser inclosos aquells pacients amb independència funcional abans de l’ictus, de territori anterior, i es van excloure els ictus menors i lacunars, entre d’altres. Per això, per portar a terme aquest projecte i superar el major factor limitant que era la mida mostral va ser imprescindible la col·laboració amb consorcis internacionals. Per elucidar la contribució genètica en el pronòstic funcional de l’ictus isquèmic, aquest treball es va realitzar a partir de quatre enfocaments diferents gràcies als últims avenços tecnològics. Primer, es va dur a terme un meta-anàlisi de diferents estudis d’associació de genoma complet (GWAS), per detectar variants comunes a la població (SNPs) associades al pronòstic als 3 mesos post-ictus (les variants més significatives van ser seleccionades per la seva replicació en un grup independent d’ictus). Després, com a tècnica complementària, es va seqüenciar tot l’exoma (WES) d’individus amb mal i bon pronòstic, per identificar variants genètiques rares. El tercer procediment va ser un estudi d’associació de l’epigenoma complet per avaluar l’estat de metilació del DNA en fase aguda en relació amb el pronòstic funcional. La quarta tècnica va consistir en un anàlisi de l’expressió gènica de les regions candidates identificades prèviament. La quantificació del pronòstic de l’ictus es va efectuar mitjançant l’escala modificada de Rankin (mRS) per neuròlegs experts. Com a resultat d’aquesta recerca es va identificar el gen PATJ fortament associat al pronòstic de l’ictus. L’estudi d’EWAS va permetre detectar tres loci, amb un candidat principal en el gen TRPV1 i a més, els anàlisis d’expressió gènica van ser consistents amb els anteriors resultats. Els resultats presentats en aquesta tesi són, a data d’avui, els primers descobriments sobre la contribució genètica en el pronòstic funcional de l’ictus a mig termini recolzats per un meta-anàlisi a nivell de genoma complet i per un estudi de metilació del DNA.
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Thraser, Adrian James. "Molecular studies towards gene therapy for chronic granulomatous disease." Thesis, University College London (University of London), 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.307515.
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Chiang, Jen-Chieh. "Dosage Compensation of Trisomy 21 and Its Implications for Hematopoietic Pathogenesis in Down Syndrome." eScholarship@UMMS, 2011. http://escholarship.umassmed.edu/gsbs_diss/931.
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Down Syndrome (DS), the most common aneuploidy seen in live-borns, is caused by trisomy for chromosome 21. DS imposes high risks for multiple health issues involving various systems of the body. The genetic complexity of trisomy 21 and natural variation between all individuals has impeded understanding of the specific cell pathologies and pathways involved. In addition, chromosomal disorders have been considered outside the hopeful progress in gene therapies for single-gene disorders. Here we test the feasibility of correcting imbalanced expression of genes across an extra chromosome by expression of a single gene, XIST, the key player in X chromosome inactivation. We targeted a large XIST transgene into one chromosome 21 in DS iPS cells, and demonstrated XIST RNA spreads and induces heterochromatin and gene silencing across that autosome in cis.
By making XIST inducible, this allows direct comparison of effects of trisomy 21 expression on cell function and phenotypes. Importantly, XIST-induction during in vitro hematopoiesis normalized excess production of differentiated blood cell types (megakaryocytes and erythrocytes), known to confer high risk for myeloproliferative disorder and leukemia. In contrast, trisomy silencing enhances production of iPS and neural stem cells, consistent with DS clinical features. Further analysis revealed that trisomy 21 initially impacts the endothelial hematopoietic transition (EHT) to generate excess CD43+ progenitors, and also increases their colony forming potential. Furthermore, results provide evidence for a key role for enhanced IGF signaling, involving over-expression of non-chromosome 21 genes controlled by trisomy 21. Finally, experiments to examine trisomy effects on angiogenesis showed no effect on production of endothelial cells, but it remains unclear whether trisomic cells may differ in ability to form vessels.
Collectively, this thesis demonstrates proof-of-principle for XIST-mediated “trisomy silencing”. Phenotypic improvement of hematopoietic and neural stem cells demonstrates the value for research into DS pathogenesis, but also provides a foundation of potential for future development of “chromosome therapy” for DS patients.
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Chiang, Jen-Chieh. "Dosage Compensation of Trisomy 21 and Its Implications for Hematopoietic Pathogenesis in Down Syndrome." eScholarship@UMMS, 2017. https://escholarship.umassmed.edu/gsbs_diss/931.
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Down Syndrome (DS), the most common aneuploidy seen in live-borns, is caused by trisomy for chromosome 21. DS imposes high risks for multiple health issues involving various systems of the body. The genetic complexity of trisomy 21 and natural variation between all individuals has impeded understanding of the specific cell pathologies and pathways involved. In addition, chromosomal disorders have been considered outside the hopeful progress in gene therapies for single-gene disorders. Here we test the feasibility of correcting imbalanced expression of genes across an extra chromosome by expression of a single gene, XIST, the key player in X chromosome inactivation. We targeted a large XIST transgene into one chromosome 21 in DS iPS cells, and demonstrated XIST RNA spreads and induces heterochromatin and gene silencing across that autosome in cis.
By making XIST inducible, this allows direct comparison of effects of trisomy 21 expression on cell function and phenotypes. Importantly, XIST-induction during in vitro hematopoiesis normalized excess production of differentiated blood cell types (megakaryocytes and erythrocytes), known to confer high risk for myeloproliferative disorder and leukemia. In contrast, trisomy silencing enhances production of iPS and neural stem cells, consistent with DS clinical features. Further analysis revealed that trisomy 21 initially impacts the endothelial hematopoietic transition (EHT) to generate excess CD43+ progenitors, and also increases their colony forming potential. Furthermore, results provide evidence for a key role for enhanced IGF signaling, involving over-expression of non-chromosome 21 genes controlled by trisomy 21. Finally, experiments to examine trisomy effects on angiogenesis showed no effect on production of endothelial cells, but it remains unclear whether trisomic cells may differ in ability to form vessels.
Collectively, this thesis demonstrates proof-of-principle for XIST-mediated “trisomy silencing”. Phenotypic improvement of hematopoietic and neural stem cells demonstrates the value for research into DS pathogenesis, but also provides a foundation of potential for future development of “chromosome therapy” for DS patients.
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Sundaram, V. "Gene therapy for inherited retinal diseases." Thesis, University College London (University of London), 2014. http://discovery.ucl.ac.uk/1418145/.
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Inherited retinal diseases include a number of disorders which typically affect photoreceptor/retinal pigment epithelial function, and can lead to severe visual impairment. Advances in molecular genetics have allowed the identification of many of the genes responsible for particular conditions, and progress in viral gene transfer technology has enabled the replacement of specific genes into the retina. The first human clinical trial of gene therapy for inherited retinal disease was carried out at Moorfields Eye Hospital and UCL Institute of Ophthalmology, involving 12 patients with RPE65 deficiency - an early-onset retinal dystrophy. The results from this trial are described and provide evidence for the safe administration of viral vectors in the eye, and also demonstrate improvements in retinal function in a number of patients. However, the extent and duration of the response did not match that observed in prior animal studies, suggesting improvements in gene expression level may be required in humans. In addition, consideration for future involvement of the foveal region is highlighted, since retinal thinning was observed in a number of patients following subretinal delivery. Achromatopsia is an inherited disorder of congenitally absent cone photoreceptor function. Gene replacement therapy in animal models of achromatopsia has shown evidence of restored cone function, suggesting that this condition may be an appropriate target for gene therapy in humans. Recent studies have suggested that achromatopsia is a progressive condition with deterioration in cone structure with age, implying that the window of opportunity for therapeutic intervention may be narrow. In this study of retinal structure and function (in preparation for a gene therapy trial) in 40 patients with achromatopsia, an age-associated deterioration in cone structure was not identified, suggesting that the age range for potential intervention is wider than recently suggested, and prospective patients should be assessed on an individual basis, irrespective of age.
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Martinico, Sandra Carmela Maria. "Assessment of gene therapy for FAP-related diseases." Thesis, Queen Mary, University of London, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.437300.
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Minas, Konstantinos. "New approaches to autoimmune therapy through gene analysis." Thesis, Available from the University of Aberdeen Library and Historic Collections Digital Resources. Restricted no access until May 19, 2011. Online version available for University member only until May 19, 2012, 2008. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?application=DIGITOOL-3&owner=resourcediscovery&custom_att_2=simple_viewer&pid=25620.
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Charo, Jehad. "Immune and gene therapies for cancer and infectious diseases /." Stockholm, 1999. http://diss.kib.ki.se/1999/91-628-3703-6/.
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Duroudier, Nathalie. "Genetic variation in the CYSLTR1 gene and allergic diseases." Thesis, University of Nottingham, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.441017.
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Brown, Iain. "Gene therapy for sporadic ovarian cancer." Thesis, University of Aberdeen, 2000. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU602008.
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Ovarian cancer accounts for more deaths than all other gynaecological cancers taken together. The 5 year survival rate can be as high as 80% for cases diagnosed early, but the asymptomatic nature of the disease means that it is most frequently detected in the later stages. By this time, disease has invariably spread beyond the ovaries and the survival rate drops to around 30%. Treatment of ovarian cancer often fails due to a high rate of chemoresistance and novel methods of treatment and detection are required to increase the survival chances of patients. This study sought to determine whether gene therapy for sporadic ovarian cancer could offer a novel and more successful treatment option for the disease. Mutation or abnormal expression of the p53 gene has already been shown to be the most common genetic even in ovarian cancer, being involved in up to 70% of cases. Wild-type p53 was delivered, using liposomes, into p53 mutant ovarian cancer cell lines and this resulted in a restoration of the wild-type functions of the gene, namely cell cycle arrest and apoptosis. The results from the cell line studies suggested that restoration of the wild-type p53 function limit or reduce tumour progression and increase the sensitivity of the tumour to chemotherapy. A mouse model of human peritoneal ovarian cancer was then constructed and the wild-type p53 gene was administered in liposomes into the peritoneum. The results suggested that p53 gene therapy prevents tumours from growing in the mice, when compared to a control gene. It is now known that p53 gene therapy for humans is being clinically assessed. There are a proportion of tumours that do not harbour an abnormal p53 gene, raising the possibility that other tumour suppressor gene mutations may play a role in the molecular genetic control of growth arrest and apoptosis. P53-dependent, apoptosis-regulating family members bcl-2 and bax were analysed immunohistochemically to determine their involvement in ovarian cancer. Both proteins were significantly associated with malignancy and also with overall length of survival, but not associated with the various prognostic factors such as stage and differentiation of tumour. It is unlikely that these genes will become targets for gene therapy in ovarian cancer. Mutation, deletion and hypermethylation of the p53-independent pi6 gene, alter its function, resulting in loss of G1 cell cycle arrest control. The status of methylation of the pi 6 promoter in ovarian tumours was determined and combined with mutation data, resulting in the conclusion that abnormal pi 6 was not a common event in ovarian cancer and is therefore not a likely candidate for gene therapy. This study has contributed to the evergrowing wealth of knowledge on the molecular genetic events of ovarian cancer, and has shown that gene therapy for sporadic ovarian cancer as a clinical application is feasible.
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Niessen, Stijn Johannes Maria. "Towards muscle-targeted-gene-therapy for human and canine diabetes mellitus." Thesis, Royal Veterinary College (University of London), 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.559063.
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Wood, David Rowe Ding Jiahuan. "Design, optimization, and evaluation of conditionally active gene therapy vectors." Waco, Tex. : Baylor University, 2008. http://hdl.handle.net/2104/5153.
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Holder, Kristina Kichler. "Dynamics of adaptive evolution in two experimental viral systems." Access restricted to users with UT Austin EID Full text (PDF) from UMI/Dissertation Abstracts International, 2001. http://wwwlib.umi.com/cr/utexas/fullcit?p3037499.
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Ayaz, Serife. "Development Of A Genetic Material Transfer Approach For Gene Therapy." Master's thesis, METU, 2005. http://etd.lib.metu.edu.tr/upload/3/12605939/index.pdf.
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This thesis is focused on the development of a gene delivery system, especially for the purpose of DNA vaccination. DNA expression vectors have the potential to be useful therapeutics for a wide variety of applications. A carrier system was designed to realize the delivery of genes to cells and the promotion of controlled adequate expression in the target cells. The low gene delivery efficiency observed with systems composed of polyplexes is mainly due to low stability of polycation e.g polyethylenimine-DNA complexes and inability of most of the complexes to the reach nucleus after entering the cells. The encapsulation of polyethylenimine-DNA complexes inside the alginate microspheres was expected to provide protection from nuclease-based attack, thereby, increasing the stability of the complex and also to achieve controlled release of the complex at the target tissue.
In this study, controlled release of complexes from alginate microspheres was studied with DNA staining. In Tris-HCl buffer, the release of PEI-DNA complexes were completed in 48 h, however in cell culture medium (DMEM) 18 % of complexes were released in 48 h because of presence of Ca+2 ions in DMEM. Also, in order to provide mucosal gene delivery for mucosal immunization polyethylene glycol (PEG) was introduced into the composition of microspheres and the two systems were compared in terms of release kinetics of the complexes. In the presence of PEG, release of PEI-DNA complexes from alginate microspheres in the cell culture medium (DMEM) were enhanced and 50 % of PEI-DNA were released from the microspheres in 48 h. To understand the effect of the PEG on the surface of microspheres zeta potential analysis and microscopic examination were carried out. By increasing percentage of PEG (0, 15, 30, 50) in microspheres, less negative zeta potential value were measured. Mucoadhesion of alginate and PEG-alginate microspheres were evaluated by using modified microbalance method, and in the presence of PEG enhancement of mucoadhesion was observed. In this way a gene delivery system with a possible route through mucosa of tissues was prepared.
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Arteaga, H. Jose. "Strategies of gene and immune therapy for tumors and viral diseases /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-528-x.
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Aints, Alar. "Vector development for suicide gene therapy /." Stockholm, 2002. http://diss.kib.ki.se/2002/91-7349-199-3.
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Fuller, Maria. "A gene transfer system derived from human immunodeficiency virus type 1 (HIV-1)." Title page, table of contents, list of abbreviations and epitome only, 2001. http://web4.library.adelaide.edu.au/theses/09PH/09phf9669.pdf.
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Kristjansdottir, Gudlaug Thora. "Genetic Variation and Expression of the IRF5 Gene in Autoimmune Diseases." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-99098.
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Aryamvally, Anjali. "Mitochondrial Replacement Therapy: Genetic Counselors’ Experiences, Knowledge and Opinions." University of Cincinnati / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1583998248123854.
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Baek, Rena C. "Therapeutic strategies for the ganglioside storage diseases." Thesis, Boston College, 2008. http://hdl.handle.net/2345/18.
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The Gangliosidoses, to include GM1 gangliosidosis and Sandhoff disease are a class of incurable lysosomal storage disorders characterized by an abnormal accumulation of gangliosides leading to progressive neurodegeneration and eventually death. GM1 gangliosidosis is caused by a genetic defect in the lysosomal-specific acid β-galactosidase, which results in the massive accumulation of ganglioside GM1 primarily in the central nervous system (CNS). Sandhoff disease (SD) results from a defect in the β-subunit of β- Hexosaminidase A and leads to the accumulation of ganglioside GM2 and its asialo derivative (GA2). As there are no effective therapies for these glycosphingolipid (GSL) storage disorders, I studied substrate reduction therapy (SRT), stem cell therapy, and adeno-associated viral (AAV) gene therapy in neonatal mice as early intervention therapies and were effective in reducing CNS GSL storage. In addition, AAV gene therapy was also evaluated in the adult GM1 gangliosidosis mice. Furthermore, analysis of the brain lipids in mice, cats, and humans with Sandhoff disease revealed that the SD cat model is intermediate between the SD mouse and the SD patient with respect to GM2 and GA2 accumulation. These findings are the first to compare the different therapies and provide valuable information for the translation of mouse studies to clinical trials in patientsThesis (PhD) — Boston College, 2008
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Biology
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Lee, Kin-wah Terence, and 李建華. "Targeted gene delivery using a receptor-mediated gene transfer system and chemosensitivity in hepatocellular carcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2000. http://hub.hku.hk/bib/B3122295X.
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The Best MPhil Thesis in the Faculties of Dentistry, Engineering, Medicine and Science (University of Hong Kong), Li Ka Shing Prizepublished_or_final_version
Pathology
Master
Master of Philosophy
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Tang, Yizhe. "Modification of adenovirus capsid proteins for gene therapy applications." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2009. https://www.mhsl.uab.edu/dt/2010r/tang.pdf.
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Brandén, Lars J. "The development of synthetic gene delivery systems /." Stockholm, 2001.
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Hunter, Michael. "Molecular investigations of the CMT4D gene N-myc downstream-regulated gene 1 (NDRG1)." University of Western Australia. School of Medicine and Pharmacology, 2006. http://theses.library.uwa.edu.au/adt-WU2007.0034.
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[Truncated abstract] Hereditary Motor and Sensory Neuropathy Lom (HMSNL) is a severe autosomal recessive peripheral neuropathy, the most common form of demyelinating Charcot-Marie-Tooth (CMT) disease in the Roma (Gypsy) population. The mutated gene, N-myc downstream-regulated gene 1 (NDRG1) on chromosome 8q24, is widely expressed and has been implicated in a wide range of processes and pathways. In this study we have aimed to assess the overall contribution of this gene to the pathogenesis of peripheral neuropathies, in cases where the most common causes of CMT disease havebeen excluded, as well as to gain clues about its function through the identification of its interactions with other proteins. Sequence analysis of NDRG1 in 104 patients with CMT disease and of diverse ethnicity identified one novel disease-causing mutation, IVS8-1G>A (g.2290787G>A), which affects the splice-acceptor site of IVS8 and results in the skipping of exon 9 . . . The results suggest a defect in Schwann cell lipid trafficking as a major pathogenetic mechanism in CMT4D. At the same time, database searches showed that the chromosomal location of NDRG1 coincides with a reported High-Density Lipoprotein-Cholesterol Quantitive Trait Locus (HDL-CQTL) in humans and in mice. A putative role of NDRG1 in the general mechanisms of HDL-mediated cholesterol transport was supported by biochemical studies of blood lipids, which revealed an association between the Gypsy founder mutation, R148X, and decreased HDL-C levels. These findings suggest that while peripheral neuropathy is the drastic result of NDRG1 deficiency, the primary role of the protein may be related to general mechanisms of lipid transport⁄metabolism.
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Jung, Cindy. "Quantitative analysis of lentivirus incorporation of heterologous viral and non-viral proteins for lung gene therapy." Diss., Atlanta, Ga. : Georgia Institute of Technology, 2007. http://hdl.handle.net/1853/26648.
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Thesis (Ph.D)--Biomedical Engineering, Georgia Institute of Technology, 2008.Committee Chair: Joseph M. Le Doux; Committee Member: Andrés J. Garcia; Committee Member: Cheng Zhu; Committee Member: Nael McCarty; Committee Member: Richard Compans. Part of the SMARTech Electronic Thesis and Dissertation Collection.
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Krishna, Delfi. "Investigation of the role of target cell factors in retrovirus transduction." Diss., Available online, Georgia Institute of Technology, 2005, 2005. http://etd.gatech.edu/theses/available/etd-11212005-102548/.
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Thesis (Ph. D.)--Chemical and Biomolecular Engineering, Georgia Institute of Technology, 2006.Harish Radhakrishna, Committee Member ; Mark Prausnitz, Committee Co-Chair ; Joseph Le Doux, Committee Chair ; Timothy Wick, Committee Member ; Richard Compans, Committee Member ; Athanassios Sambanis, Committee Member.
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Furlan, Roberto. "Development of herpesvirus-based vectors for the treatment of central nervous system autoimmune diseases." Thesis, Open University, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.342890.
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Eleftheriadou, Ioanna. "Development of novel targeted lentiviral vectors for gene therapy of motor neuron diseases." Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/27243.
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Motor Neuron Diseases (MND) including Amyotrophic Lateral Sclerosis (ALS) and Spinal Muscular Atrophy (SMA) are neurodegenerative diseases that can cause progressive paralysis and premature death, while there are no treatments available up to date. Gene therapy using lentiviruses has been successful at alleviating symptoms and extending survival in murine models of both. Restricting transduction to specific cells, is critical for safe and efficient gene therapy. The aim of this study was to generate novel lentiviral vectors with tropism to motor neurons (MNs) using surface engineering, that involves incorporation of a fusogenic glycoprotein (mutated sindbis G) and an antibody recognizing a cell-surface receptor, onto the lentiviral surface. Antibodies against rat Thy1.1, rat p75NTR (Low Affinity Nerve Growth Factor Receptor) and mouse CAR (Coxsackie and adenovirus receptor) receptors expressed on the presynaptic terminal of the neuromuscular junction (NMJ) were cloned and used to surface engineer high titer lentiviral vectors ( Thy1.1, p75NTR and CAR). These vectors preferentially transduced cell lines expressing these receptors and primary motor neuron cultures compared to non-targeted controls. The ability of these vectors to be transported retrogradely and transduce MNs was demonstrated in vitro in compartmented microfluidic cultures in fixed and live imaging experiments. Tropism of these vectors was assessed in vivo in the rat brain following intrastiatal injections. In vivo intramuscular delivery of CAR targeted lentiviral vectors in tibialis anterior of mice lead to transduction of motor neurons in ventral spinal cord. Transduction of spinal cord was further demonstrated by in vivo bioluminescence imaging studies in mice injected intramuscularly with the CAR targeted vectors. This is the first ever demonstration that surface engineering can confer novel trafficking and transduction characteristics to lentiviral vectors. These targeted lentiviral vectors have superior trafficking, transduction and specificity for MNs than previously used lentiviral vectors, making them good candidates for non-invasive CNS -targeted delivery of therapeutics in MN diseases.
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Svahn, Mathias G. "DNA analogs for the purpose of gene therapy /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-290-3/.
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Dokka, Sujatha. "IL-10 gene therapy for the treatment of pulmonary inflammation." Morgantown, W. Va. : [West Virginia University Libraries], 2000. http://etd.wvu.edu/templates/showETD.cfm?recnum=1421.
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Thesis (Ph. D.)--West Virginia University, 2000.Title from document title page. Document formatted into pages; contains ix, 132 p. : ill. (some col.) Vita. Includes abstract. Includes bibliographical references.
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Yip, Yim-ling, and 葉艷玲. "Immortalization of human nasopharyngeal epithelial cells by defined genetic elements." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B39557522.
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Wong, Tik-wun Lina, and 黃荻媛. "Construction of an infectious PRRSV cDNA clone and its use as a vectorfor foreign gene expression." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hub.hku.hk/bib/B44251841.
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Landazuri, Natalia. "Enhanced gene transfer using polymer-complexed retrovirus vectors." Thesis, Georgia Institute of Technology, 2001. http://hdl.handle.net/1853/20677.
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Frida, Jonsson. "Underlying genetic mechanisms of hereditary dystrophies in retina and cornea." Doctoral thesis, Umeå universitet, Institutionen för medicinsk biovetenskap, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-130538.
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Inherited retinal and corneal dystrophies represent a group of disorders with great genetic heterogeneity. Over 250 genes are associated with retinal diseases and 16 genes are causative of corneal dystrophies. This thesis is focused on finding the genetic causes of corneal dystrophy, Leber congenital amaurosis (LCA), Stargardt disease and retinitis pigmentosa in families from northern Sweden. By whole exome sequencing a novel mutation, c.2816C>T, p.Thr939Ile, in Collagen Type XVII, Alpha 1 chain, COL17A1, gene was identified in several families with epithelial recurrent erosion dystrophy (ERED). We showed that the COL17A1 protein is expressed in the basement membrane of the cornea, explaining the mutation involvement in the corneal symptoms. We could link all the families in this study to a couple born in the late 1700s confirming a founder mutation in northern Sweden. Our finding highlights role of COL17A1 in ERED and suggests screening of this gene in patients with similar phenotype worldwide. Furthermore the genetic causes in several retinal degenerations were identified. In one family with two recessive disorders, LCA and Stargardt disease, a novel stop mutation, c.2557C>T, p.Gln853Stop, was detected in all LCA patients. In the Stargardt patients two intronic variants, the novel c.4773+3A>G and c.5461-10T>C, were detected in the ABCA4 gene. One individual was homozygous for the known variant c.5461-10T>C and the other one was compound heterozygote with both variants present. Both variants, c.4773+3A>G and c.5461-10T>C caused exon skipping in HEK293T cells demonstrated by in vitro splice assay, proving their pathogenicity in Stargardt disease. Finally, in recessive retinitis pigmentosa, Bothnia Dystrophy (BD), we identified a second mutation in the RLBP1 gene, c.677T>A, p.Met226Lys. Thus, BD is caused not only by common c.700C>T variant but also by homozygosity of c.677T>A or compound heterozygosity. Notably, known variant, c.40C>T, p.R14W in the CAIV gene associated with a dominant retinal dystrophy RP17 was detected in one of the compound BD heterozygote and his unaffected mother. This variant appears to be a benign variant in the population of northern Sweden. In conclusion, novel genetic causes of retinal dystrophies in northern Sweden were found demonstrating the heterogeneity and complexity of retinal diseases. Identification of the genetic defect in COL17A1 in the corneal dystrophy contributes to understanding ERED pathogenesis and encourages refinement of IC3D classification. Our results provide valuable information for future molecular testing and genetic counselling of the families.
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Myhre, Susanna. "Genetic re-targeting and de-targeting of adenovirus type 5 in order to create vectors for gene therapy /." Göteborg : Department of Microbiology and Immunology, The Sahlgrenska Academy at Göteborg University, 2007. http://hdl.handle.net/2077/7498.
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Chan, Fu-lun, and 陳賦麟. "Effective DNA delivery mediated by pH responsive peptides." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B48333335.
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Non-viral vectors have been used to deliver therapeutic genes to treat different diseases. There are a variety of non-viral vectors such as liposomes, cationic polymers and peptides. Among all, pH responsive peptides showed excellent DNA transfection efficiency in many types of cell. These peptides are capable of changing their structural conformation as pH decreases, adopting a disordered structure which can destabilize endosomal membrane and therefore enhancing the release of DNA from endosomes into cytosol.
Traditional pH responsive histidine-rich peptides showed good DNA transfection efficiency and low toxicity to the cells when compared with other non-viral vectors. However, their low pKa value restricted these peptides to be protonated only at late endosomal stage, in which DNA is extremely susceptible to endosomal degradation. This hindered the DNA to be released to the cytosol efficiently and therefore reduced DNA transfection efficiency. In response to this, it is of great interest to probe into the insertion of either 2,3-diaminopropionic acid (Dap) or methylated-2,3-diaminopropionic acid Dap(Me) to the peptide as alternative pH sensitive components. The pKa values for both Dap and Dap(Me) peptides are higher than that of histidine. It is anticipated that the higher pKa value, the protonation of peptide could be happened at an earlier stage of endosomal maturation. Such protonation of peptide destabilizes the endosome membrane rapidly, causing the release of DNA to the cytosol effectively and hence improving DNA transfection efficiency.
In this experiment, LADap(Me)4-L1 peptide was the optimal candidate within the series. It showed good DNA transfection efficiency and cell viability in A549 cells among all Dap and Dap(Me) peptides.published_or_final_version
Pharmacology and Pharmacy
Master
Master of Medical Sciences