Relevant bibliographies by topics / Adeno-Associated Viral (AAV) vectors

Academic literature on the topic 'Adeno-Associated Viral (AAV) vectors'

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Published: 11 March 2023

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Journal articles on the topic "Adeno-Associated Viral (AAV) vectors"

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Bartlett, Jeffrey S., Rose Wilcher, and R. Jude Samulski. "Infectious Entry Pathway of Adeno-Associated Virus and Adeno-Associated Virus Vectors." Journal of Virology 74, no. 6 (March 15, 2000): 2777–85. http://dx.doi.org/10.1128/jvi.74.6.2777-2785.2000.

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ABSTRACT We have investigated the infectious entry pathway of adeno-associated virus (AAV) and recombinant AAV vectors by assessing AAV-mediated gene transfer and by covalently conjugating fluorophores to AAV and monitoring entry by fluorescence microscopy. We examined AAV entry in HeLa cells and in HeLa cell lines which inducibly expressed a dominant interfering mutant of dynamin. The data demonstrate that AAV internalizes rapidly by standard receptor-mediated endocytosis from clathrin-coated pits (half-time <10 min). The lysosomotropic agents ammonium chloride and bafilomycin A1 prevent AAV-mediated gene transfer when present during the first 30 min after the onset of endocytosis, indicating that AAV escapes from early endosomes yet requires an acidic environment for penetration into the cytosol. Following release from the endosome, AAV rapidly moves to the cell nucleus and accumulates perinuclearly beginning within 30 min after the onset of endocytosis. We present data indicating that escape of AAV from the endosome and trafficking of viral particles to the nucleus are unaffected by the presence of adenovirus, the primary helper virus for a productive AAV infection. Within 2 h, viral particles could be detected within the cell nucleus, suggesting that AAV enters the nucleus prior to uncoating. Interestingly, the majority of the intracellular virus particles remain in a stable perinuclear compartment even though gene expression from nuclear AAV genomes can be detected. This suggests that the process of nuclear entry is rate limiting or that AAV entry involves multiple pathways. Nevertheless, these data establish specific points in the AAV infectious entry process and have allowed the generation of a model for future expansion to specific cell types and AAV vector analysis in vivo.
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Lieber, André, Dirk S. Steinwaerder, Cheryl A. Carlson, and Mark A. Kay. "Integrating Adenovirus–Adeno-Associated Virus Hybrid Vectors Devoid of All Viral Genes." Journal of Virology 73, no. 11 (November 1, 1999): 9314–24. http://dx.doi.org/10.1128/jvi.73.11.9314-9324.1999.

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ABSTRACT Recently, we demonstrated that inverted repeat sequences inserted into first-generation adenovirus (Ad) vector genomes mediate precise genomic rearrangements resulting in vector genomes devoid of all viral genes that are efficiently packaged into functional Ad capsids. As a specific application of this finding, we generated adenovirus–adeno-associated virus (AAV) hybrid vectors, first-generation Ad vectors containing AAV inverted terminal repeat sequences (ITRs) flanking a reporter gene cassette inserted into the E1 region. We hypothesized that the AAV ITRs present within the hybrid vector genome could mediate the formation of rearranged vector genomes (ΔAd.AAV) and stimulate transgene integration. We demonstrate here that ΔAd.AAV vectors are efficiently generated as by-products of first-generation adenovirus-AAV vector amplification. ΔAd.AAV genomes contain only the transgene flanked by AAV ITRs, Ad packaging signals, and Ad ITRs. ΔAd.AAV vectors can be produced at a high titer and purity. In vitro transduction properties of these deleted hybrid vectors were evaluated in direct comparison with first-generation Ad and recombinant AAV vectors (rAAVs). The ΔAd.AAV hybrid vector stably transduced cultured cells with efficiencies comparable to rAAV. Since cells transduced with ΔAd.AAV did not express cytotoxic viral proteins, hybrid viruses could be applied at very high multiplicities of infection to increase transduction rates. Southern analysis and pulsed-field gel electrophoresis suggested that ΔAd.AAV integrated randomly as head-to-tail tandems into the host cell genome. The presence of two intact AAV ITRs was crucial for the production of hybrid vectors and for transgene integration. ΔAd.AAV vectors, which are straightforward in their production, represent a promising tool for stable gene transfer in vitro and in vivo.
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Xuan, Keh Min, Nur Ain Mohd Asri, Rafeah Suppian, Norazmi Mohd Nor, Maryam Azlan, and Frank Camacho. "The Use of Adeno-associated virus (AAV) in Vaccine Development." Asian Journal of Medicine and Biomedicine 6, S1 (November 10, 2022): 192–93. http://dx.doi.org/10.37231/ajmb.2022.6.s1.583.

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Adeno-associated virus (AAV) is a very tiny (20-26 nm) icosahedral and non-enveloped virus, and it belongs to the Parvoviridae family. AAV vectors are the most widely used option for gene therapy and delivery of therapeutic antibodies due to their relatively low immunogenicity, high safety profile, broad tropism, and their tendency to maintain long-term gene expression [1]. AVV vectors are developed by transfection of human embryonic kidney (HEK) 293 T cells with transgene, packaging and helper plasmids [2]. Several clinical studies have investigated the use of AAV vectors for gene therapy in treating of Parkinson’s disease, Alzheimer’s disease, heart disease, and prostate cancer [3]. AAV vectors have previously been used to treat muscular diseases, but in recent years, their usage as vaccine vectors to cure or prevent infectious diseases including HIV, HPV, and influenza has expanded [4]. Here, we discuss the advantages and disadvantages of the use of AAV in vaccine development, and future approaches in improving the drawbacks caused by AAV-based vaccines. Numerous animal investigations have been conducted to explore vaccine vectors against various illnesses, suggesting a possibility for AAV-based vaccinations. Clinical studies on humans are, however, uncommon because, in contrast to other viral vectors, AAV induces a poor humoral and cellular immune response. Additionally, infectious vaccinations often target a large group of healthy individuals across a variety of ages, including children and teenagers. Therefore, compared to AAV-based gene therapies, vaccinations based on AAV vectors need to be more cost-effective and need more robust safety control. According to several research, AAV vector vaccines have been shown to induce a stronger or longer lasting antibody response in comparison to other vaccination approaches, such as DNA, recombinant proteins, inactivated viruses, or virus-like particles (VLPs) [5]. However, AAV vectors are thought to have a low immunogenic profile in comparison to other viral vectors. The main limitations of AAV vectors are their low transgenic capacity and widespread pre-existing immunity in humans [6]. Currently, strategies for improving AAV immunogenicity and circumventing pre-existing immunity are actively being investigated. The research undertaken so far have highlighted numerous significant benefits of AAV vectors for immunisation. Despite all the advantages, there are still a variety of challenges that limit the use of these vectors as a vaccine in humans. Thus, it is necessary to overcome these challenges in order to make AAV-based vaccines effective.
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Gonçalves, Manuel A. F. V., Ietje van der Velde, Josephine M. Janssen, Bram T. H. Maassen, Evert H. Heemskerk, Dirk-Jan E. Opstelten, Shoshan Knaän-Shanzer, Dinko Valerio, and Antoine A. F. de Vries. "Efficient Generation and Amplification of High-Capacity Adeno-Associated Virus/Adenovirus Hybrid Vectors." Journal of Virology 76, no. 21 (November 1, 2002): 10734–44. http://dx.doi.org/10.1128/jvi.76.21.10734-10744.2002.

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ABSTRACT Effective gene therapy is dependent on safe gene delivery vehicles that can achieve efficient transduction and sustained transgene expression. We are developing a hybrid viral vector system that combines in a single particle the large cloning capacity and efficient cell cycle-independent nuclear gene delivery of adenovirus (Ad) vectors with the long-term transgene expression and lack of viral genes of adeno-associated virus (AAV) vectors. The strategy being pursued relies on coupling the AAV DNA replication mechanism to the Ad encapsidation process through packaging of AAV-dependent replicative intermediates provided with Ad packaging elements into Ad capsids. The generation of these high-capacity AAV/Ad hybrid vectors takes place in Ad early region 1 (E1)-expressing cells and requires an Ad vector with E1 deleted to complement in trans both AAV helper functions and Ad structural proteins. The dependence on a replicating helper Ad vector leads to the contamination of AAV/Ad hybrid vector preparations with a large excess of helper Ad particles. This renders the further propagation and ultimate use of these gene delivery vehicles very difficult. Here, we show that Cre/loxP-mediated genetic selection against the packaging of helper Ad DNA can reduce helper Ad vector contamination by 99.98% without compromising hybrid vector rescue. This allowed amplification of high-capacity AAV/Ad hybrid vectors to high titers in a single round of propagation.
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Favaro, Patricia, Harre D. Downey, Federico Mingozzi, Fraser Wright, Bernd Hauck, Katherine A. High, and Valder R. Arruda. "Safety of Recombinant Adeno-Associated Viral Vectors in a Large Animal Model." Blood 110, no. 11 (November 16, 2007): 2586. http://dx.doi.org/10.1182/blood.v110.11.2586.2586.

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Abstract Recombinant adeno-associated viral (AAV) vector is a promising gene-based strategy for the treatment of several inherited diseases. Using AAV serotype 2 (AAV-2), the most common tested vector in humans, we have determined that the risk of germline transmission and the immune responses to both transgene product and/or vector-capsid proteins are critical obstacles to the safety of this strategy (Nat Med12:342, 2006). Recently, novel and more potent serotypes have emerged such as AAV-8 that allows efficient liver transduction following peripheral intravenous injection (IV). The major determinant of vector safety relies on its tissue tropism. Here, we sought to compare the efficacy and safety profile of AAV-2 and AAV-8 in a large animal model. Male rabbits (∼3 kg) received IV injection of AAV-2 (n=11) or AAV-8 (n=11) encoding human F.IX (hF.IX) at doses ranging from 1×1012 to 1×1013vg/kg. Injections with AAV-2-hF.IX resulted in 6-fold lower expression of hF.IX than AAV-8-hF.IX for both low and high dose cohorts. Notably, no neutralizing antibody to hF.IX was detected with either serotypes. Eighteen weeks following the initial injections, animals were cross-administered with either AAV-2 or AAV-8. Whereas injection of AAV-8 led a 20% increase in transgene expression in animals initially injected with AAV-2-h.FIX, AAV-2 failed to boost hF.IX expression. Regarding germline safety, the presence of vector genomes in semen samples from the high-dose cohort (6 to 10 weeks after injection) was 3-5 fold higher for AAV-8 compared with AAV-2. There were no differences in the vector clearance in the semen among rabbits from the low-dose cohorts of AAV-2 and AAV-8. After 12 weeks, all semen samples from all cohorts tested negative. In another rabbit model, vasectomized prior to vector injection, we determined that semen samples lacking germ cells were also positive for vector-DNA sequences. The kinetics of vector clearance in these samples was dose- and time-dependent and serotype-independent. Because the presence of capsid in early-time points is critical for predicting possible immune responses against the viral vector, we determine the vector biodistribution one week after injection of 1×1013 vg/kg of AAV-2 or AAV-8. Rabbits were euthanized and their organs were harvested and analyzed for vector DNA presence through real-time quantitative PCR. Comparing to AAV-2, AAV-8 genomes were 2-5 fold times higher in all organs (spleen, lung, heart, and kidney), with the exception of liver where vector-DNA content was comparable (range from 25-69 copy number/cell). In addition, testes, accessory glands, and prostates were positive for the vector DNA, albeit in very low levels (the highest level of vector DNA found in those organs was 3copy number/cell in the testis of one rabbit injected with AAV-8). These differences may reflect the distributions of cellular receptors for AAV-2 and AAV-8, which may also explain the higher content of vector genome in the semen of high-dose AAV-8 cohort. Together our findings suggest that AAV-8 ensures higher transgene expression than AAV-2 and preexisting immunity to AAV-2, a naturally acquired virus in humans, may not limit AAV-8-mediated gene delivery. The overall kinetics of AAV vector clearance in the semen seems to be independent of the presence of germ cells and vector serotype. However, early biodistribution data of AAV-8 suggests a distinct safety profile from AAV-2.
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Yan, Ziying, Roman Zak, Yulong Zhang, and John F. Engelhardt. "Inverted Terminal Repeat Sequences Are Important for Intermolecular Recombination and Circularization of Adeno-Associated Virus Genomes." Journal of Virology 79, no. 1 (January 1, 2005): 364–79. http://dx.doi.org/10.1128/jvi.79.1.364-379.2005.

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ABSTRACT The relatively small package capacity (less than 5 kb) of adeno-associated virus (AAV) vectors has been effectively doubled with the development of dual-vector heterodimerization approaches. However, the efficiency of such dual-vector systems is limited not only by the extent to which intermolecular recombination occurs between two independent vector genomes, but also by the directional bias required for successful transgene reconstitution following concatemerization. In the present study, we sought to evaluate the mechanisms by which inverted terminal repeat (ITR) sequences mediate intermolecular recombination of AAV genomes, with the goal of engineering more efficient vectors for dual-vector trans-splicing approaches. To this end, we generated a novel AAV hybrid-ITR vector characterized by an AAV-2 and an AAV-5 ITR at opposite ends of the viral genome. This hybrid genome was efficiently packaged into either AAV-2 or AAV-5 capsids to generate infectious virions. Hybrid AV2:5 ITR viruses had a significantly lower capacity to form circular intermediates in infected cells than homologous AV2:2 and AV5:5 ITR vectors despite their similar capacity to express an encoded enhanced green fluorescent protein (EGFP) transgene. To examine whether the divergent ITR sequences contained within hybrid AV2:5 ITR vectors could direct intermolecular recombination in a tail-to-head fashion, we generated two hybrid ITR trans-splicing vectors (AV5:2LacZdonor and AV2:5LacZacceptor). Each delivered one exon of a β-galactosidase minigene flanked by donor or acceptor splice sequences. These hybrid trans-splicing vectors were compared to homologous AV5:5 and AV2:2 trans-splicing vector sets for their ability to reconstitute β-galactosidase gene expression. Results from this comparison demonstrated that hybrid ITR dual-vector sets had a significantly enhanced trans-splicing efficiency (6- to 10-fold, depending on the capsid serotype) compared to homologous ITR vectors. Molecular studies of viral genome structures suggest that hybrid ITR vectors provide more efficient directional recombination due to an increased abundance of linear-form genomes. These studies provide direct evidence for the importance of ITR sequences in directing intermolecular and intramolecular homologous recombination of AAV genomes. The use of hybrid ITR AAV vector genomes provides new strategies to manipulate viral genome conversion products and to direct intermolecular recombination events required for efficient dual-AAV vector reconstitution of the transgene.
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Mingozzi, Federico, Jörg Schüttrumpf, Valder R. Arruda, Yuhong Liu, Yi-Lin Liu, Katherine A. High, Weidong Xiao, and Roland W. Herzog. "Improved Hepatic Gene Transfer by Using an Adeno-Associated Virus Serotype 5 Vector." Journal of Virology 76, no. 20 (October 15, 2002): 10497–502. http://dx.doi.org/10.1128/jvi.76.20.10497-10502.2002.

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ABSTRACT Adeno-associated viral (AAV) vectors have been shown to direct stable gene transfer and expression in hepatocytes, which makes them attractive tools for treatment of inherited disorders such as hemophilia B. While substantial levels of coagulation factor IX (F.IX) have been achieved using AAV serotype 2 vectors, use of a serotype 5 vector further improves transduction efficiency and levels of F.IX transgene expression by 3- to 10-fold. In addition, the AAV-5 vector transduces a higher proportion of hepatocytes (∼15%). The subpopulations of hepatocytes transduced with either vector widely overlap, with the AAV-5 vector transducing additional hepatocytes and showing a wider area of transgene expression throughout the liver parenchyma.
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Hanazono, Yutaka, Kevin E. Brown, Atsushi Handa, Mark E. Metzger, Dominik Heim, Gary J. Kurtzman, Robert E. Donahue, and Cynthia E. Dunbar. "In Vivo Marking of Rhesus Monkey Lymphocytes by Adeno-Associated Viral Vectors: Direct Comparison With Retroviral Vectors." Blood 94, no. 7 (October 1, 1999): 2263–70. http://dx.doi.org/10.1182/blood.v94.7.2263.419k36_2263_2270.

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We have compared adeno-associated virus (AAV)-based and retrovirus-based vectors for their ability to transduce primary T lymphocytes in vitro and then tracked the persistence of these genetically marked lymphocytes in vivo, using the rhesus monkey model. To avoid the complication of immune rejection of lymphocytes transduced with xenogeneic genes in tracking studies primarily designed to investigate transduction efficiency and in vivo kinetics, the vectors were designed without expressed genes. All vectors contained identically mutated β-galactosidase gene (β-gal) and neomycin resistance gene (neo) DNA sequences separated by different length polylinkers, allowing simple differentiation by polymerase chain reaction (PCR). Each of 2 aliquots of peripheral blood lymphocytes from 4 rhesus monkeys were transduced with either AAV or retroviral vectors. The in vitro transduction efficiency (mean vector copy number/cell) after the ex vivo culture was estimated by PCR at 0.015 to 3.0 for AAV, varying depending on the multiplicity of infection (MOI) used for transduction, and 0.13 to 0.19 for the retroviral transductions. Seven days after transduction, Southern blot analysis of AAV-transduced lymphocytes showed double-stranded and head-to-tail concatemer forms but failed to show integration of the AAV vector. AAV and retroviral aliquots were reinfused concurrently into each animal. Although the retrovirally marked lymphocytes could be detected for much longer after infusion, AAV transduction resulted in higher short-term in vivo marking efficiency compared with retroviral vectors, suggesting possible clinical applications of AAV vectors in lymphocyte gene therapy when long-term vector persistence is not required or desired.
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Jewell, Andrew P., Melanie Cochrane, Jenny McIntosh, Reuben Benjamin, and Amit Nathwani. "Comparison of Viral Vectors for Gene Transfer into CLL Cells: Efficient Transduction with Adeno-Associated Virus-8 (AAV-8)." Blood 106, no. 11 (November 16, 2005): 2985. http://dx.doi.org/10.1182/blood.v106.11.2985.2985.

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Abstract Chronic Lymphocytic Leukaemia (CLL) remains largely incurable despite recent advances in therapy, and therefore alternative strategies are of interest in treating this disease. One such alternative is the use of gene therapy, but this relies on developing efficient gene transfer technologies. We have compared several viral vectors coding for green fluorescent protein (GFP) for their ability to transduce CLL cells. Three serotypes of adeno-associated virus (AAV) were used, AAV-2, AAV-5 and a relatively new isolate AAV-8, an EI-EIII deleted adenoviral 5 based vector, AV-5, all with GFP regulated by the CMV promoter, and a VSVG pseudotyped lentiviral vector in which GFP expression is controlled by EF1a promotor/enhancer complex. AV-5 resulted in variable GFP expression, 24.1±3.4%, n=10 but caused cell death at high multiplicities of infection (MOI). The lentiviral vector resulted in GFP expression of 23.5±2.6%, n=12, at the highest titre used, and expression declined in a distinct dose-dependent manner as titres were reduced. Of the AAV vectors, AAV-8 was the most efficient with GFP expression at 41.3±1.0% n=14. We conclude that AAV-8 is a promising viral vector for efficient transduction of CLL cells. Figure 1. Percentage GFP expression for three viral vectors. Three different MOI’s were used at log dilutions. Figure 1. Percentage GFP expression for three viral vectors. Three different MOI’s were used at log dilutions.
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Monahan, Paul E., Claude Négrier, Michael Tarantino, Leonard A. Valentino, and Federico Mingozzi. "Emerging Immunogenicity and Genotoxicity Considerations of Adeno-Associated Virus Vector Gene Therapy for Hemophilia." Journal of Clinical Medicine 10, no. 11 (June 2, 2021): 2471. http://dx.doi.org/10.3390/jcm10112471.

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Adeno-associated viral (AAV) vector gene therapy has shown promise as a possible cure for hemophilia. However, immune responses directed against AAV vectors remain a hurdle to the broader use of this gene transfer platform. Both innate and adaptive immune responses can affect the safety and efficacy of AAV vector–mediated gene transfer in humans. These immune responses may be triggered by the viral capsid, the vector’s nucleic acid payload, or other vector contaminants or excipients, or by the transgene product encoded by the vector itself. Various preclinical and clinical strategies have been explored to overcome the issues of AAV vector immunogenicity and transgene-related immune responses. Although results of these strategies are encouraging, more efficient approaches are needed to deliver safe, predictable, and durable outcomes for people with hemophilia. In addition to durability, long-term follow-up of gene therapy trial participants will allow us to address potential safety concerns related to vector integration. Herein, we describe the challenges with current methodologies to deliver optimal outcomes for people with hemophilia who choose to undergo AAV vector gene therapy and the potential opportunities to improve on the results.
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Dissertations / Theses on the topic "Adeno-Associated Viral (AAV) vectors"

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Lauramore, Amanda K. "Retinal cell tropism of adeno-associated viral (aav) vector serotypes." [Gainesville, Fla.] : University of Florida, 2004. http://purl.fcla.edu/fcla/etd/UFE0005301.

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Thesis (M.S.)--University of Florida, 2004.
Typescript. Title from title page of source document. Document formatted into pages; contains 71 pages. Includes Vita. Includes bibliographical references.
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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.

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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, 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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Steines, Benjamin Richard. "Investigation and application of novel adeno-associated viral vectors for cystic fibrosis gene therapy." Diss., University of Iowa, 2015. https://ir.uiowa.edu/etd/1763.

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Cystic Fibrosis (CF) is a lethal autosomal recessive genetic disorder caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR transports anions at the apical surface of epithelial membranes and functions in many areas of the body. However in CF, loss of CFTR function in the lungs is the major source of morbidity and mortality. Replacing the defective CFTR in the lungs through gene therapy has the potential to cure the disease. Recombinant adeno-associated virus (AAV) is an effective gene transfer vector and has been used extensively to deliver genes to cells in culture. A number of clinical trials using AAV have been attempted for a variety of diseases, including CF, albeit with limited success. Poor vector transduction efficiency prevents effective gene therapy. We have previously used a technique to greatly increase the transduction efficiency of AAV in human lung tissues by selecting from a library of AAVs using a directed evolution technique. However, this evolution was performed in cultured cells and did not fully represent the in vivo environment in which the AAV would be used. In 2008, a CF pig model was developed to develop a further understanding of the mechanisms of CF and CFTR function. We hypothesized that we could use directed evolution to select for a vector in vivo using the pig, allowing gene therapy studies to be conducted in a physiologically relevant model of CF. We selected a novel AAV variant, called AAV2H22, which is closely related to AAV2 but with greatly increased transduction efficiency in pig airway epithelia. AAV2H22 displayed specific tropism for pig airway epithelia and saturated cell surface receptors, indicating specific binding in those cells. We found that AAV2H22-mediated gene transfer corrected chloride and bicarbonate transport defects both in vitro and in vivo. Importantly, bicarbonate transport was sufficient to normalize pH in the airway surface liquid, resulting in increased bacterial killing likely due to increased activity of antimicrobial peptides. To investigate the mechanics of the increased transduction of AAV2H22, capsid mutants were assayed for transduction efficiency. Two of the five amino acid differences between AAV2 and AAV2H22 lie at the surface and are predicted to alter capsid binding. This is consistent with the results showing specific binding in cultured airway epithelia. This research has important implications for gene therapy and investigations using AAV2H22 will increase our understanding of the biology needed to successfully treat CF.
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Ibraheim, Raed R. "Genome Engineering Goes Viral: Repurposing of Adeno-associated Viral Vectors for CRISPR-mediated in Vivo Genome Engineering." eScholarship@UMMS, 2020. https://escholarship.umassmed.edu/gsbs_diss/1114.

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One of the major challenges facing medicine and drug discovery is the large number of genetic diseases caused by inherited mutations leading to a toxic gain-of-function, or loss-of-function of the disease protein. Microbiology offered a new glimpse of hope to address those disorders with the adaptation of the bacterial CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) defense system as a genome editing tool. Cas9 is a unique CRISPR-associated endonuclease protein that can be easily programmed with an RNA [a single-guide RNA (sgRNA)] that is complementary to nearly any DNA locus. Cas9 creates a double-stranded break (DSB) that can be exploited to knock out toxic genes or replenish therapeutic expression levels of essential proteins. In addition to a matching sgRNA sequence, Cas9 requires the presence of a short signature sequence [a protospacer adjacent motif (PAM)] flanking the target locus. Over the past few years, several Cas9-based therapeutic platforms have emerged to correct DNA mutations in a wide range of mammalian cell lines, ex vivo, and in vivo by adapting recombinant adeno-associated virus (rAAV). However, most of the applications of Cas9 in the field have been limited to Streptococcus pyogenes (SpyCas9), which, in its wild-type form, suffers from inaccurate editing at off-target sites. It is also difficult to deliver via an all-in-one (sgRNA+Cas9) rAAV approach due to its large size. In this thesis, I describe other Cas9 nucleases and their development as new AAV-based genome editing platforms for therapeutic editing in vivo in mouse disease models. In the first part of this thesis, I develop the all-in-one AAV strategy to deliver a Neisseria meningitidis Cas9 ortholog (Nme1Cas9) in mice to reduce the level of circulating cholesterol in blood. I also help characterize an enhanced Cas9 from another meningococcus strain (Nme2Cas9) and show that it is effective in performing editing not only in mammalian cell culture, but also in vivo by all-in-one AAV delivery. Additionally, I describe two AAV platforms that enable advanced editing modalities in vivo: 1) segmental DNA deletion by delivering two sgRNAs (along with Nme2Cas9) in one AAV, and 2) precise HDR-based repair by fitting Nme2Cas9, sgRNA and donor DNA within a single AAV capsid. Using these tools, we successfully treat two genetic disorders in mice, underscoring the importance of this powerful duo of AAV and Cas9 in gene therapy to advance novel treatment. Finally, I present preliminary data on how to use these AAV.Nme2Cas9 vectors to treat Alexander Disease, a rare progressive neurological disorder. These findings provide a platform for future application of gene editing in therapeutics.
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Moimas, Silvia. "A gene transfer approach, based on Adeno-Associated Viral (AAV) vectors, to study the process of vessel maturation and stabilization." Doctoral thesis, Università degli studi di Trieste, 2009. http://hdl.handle.net/10077/3311.

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2007/2008
The main goal of angiogenic gene therapy is the formation of functional new blood vessels adequate to restore blood flow in ischemic tissues. Angiogenesis is a complex process, consisting in the sprouting of new capillaries from pre-existing vessels to form an immature vascular network, which subsequently undergoes functional maturation and remodelling. Many factors are involved in this process and, among them, the VEGF family members are universally recognized as the key players. During my PhD I exploited gene transfer by vectors based on the Adeno-Associated Virus (AAV) to express several factors involved in the angiogenic process, in an attempt to define the molecular and cellular mechanisms of vessel maturation and stabilization. Most experiments were performed by vector injection in the mouse and rat skeletal muscle, followed by detailed histological, immunohistochemical and functional analysis. First of all the angiogenic effect driven by two main VEGF isoforms, VEGF165 and VEGF121 was compared. AAV-VEGF165 and AAV-VEGF121 appeared equally able to induce endothelial cell proliferation, leading to the formation of new CD31 positive capillaries. However, only the longest VEGF165 isoform was capable to recruit -SMA positive cells around growing capillaries and therefore giving rise to small arteries. The acquisition of a smooth muscle cell layer can be considered as marker of vessel maturation. This was also confirmed by a permeability assay, which showed that VEGF121-induced vessels were more permeable compared to those induced by VEGF165. Interestingly, the presence of -SMA positive vessels was paralleled by the recruitment of CD11b positive mononuclear cells from the bone marrow, cells which were not recruited by VEGF121. The presence of these infiltrating cells in close proximity to the newly formed arterioles suggested their possible role in smooth muscle cell recruitment and vessel maturation. Real-time PCR allowed observing that the infiltrating CD11b positive cells expressed a cocktail of cytokines implicated in vessel maturation, such as TGF- and PDGF-B. As a proof of concept of the paracrine activity of these cells in vessel maturation, we developed an AAV-PDGF-B vector, which, when co-injected with AAV-VEGF121, was arteriogenic even in absence of cellular infiltration. Thus, the expression of PDGF-B partially substitutes for the cells observed in the muscles injected by AAV-VEGF165 to form arterial vessels. To verify the functionality of the vessels induced by AAV-VEGF165 we delivered this vector to different animal models of tissue ischemia: a flap ischemia model and an in vivo chamber for tissue engineering based on an artero-venous loop. In both the models, VEGF165 expression induced the formation of -SMA positive vessels, which turned out to improve flap survival in the flap models, and to promote the formation of new vascularized tissue in the chamber. Despite the presence of several arteries, other vessels formed by VEGF165 were abnormally enlarged and leaky, often forming vascular lacunae. This observation indicated that VEGF gene transfer might not be sufficient for the formation of a fully functional vascular network, and that other factors might be required in order to achieve functional competence of the neovessels. We observed that the combined expression of VEGF165 with Angiopoietin-1, which is known to stabilize endothelial and mural cell interactions, resulted in a significant reduction of vessel permeability and improved blood flow, as assessed by positron emission tomography (PET) and single photon emission tomography (SPECT). These findings reveal that a fine control of the expression of angiogenic factors is needed to achieve the formation of stable and functional vessels. The presence of -SMA positive cells might be considered as a first step in vessel maturation but further stabilization factors have to take part to the process in order to tighten the cell-cell junctions. Moreover, we showed that a detailed histological and functional analysis ex vivo might not be sufficient to characterized the new vasculature, requiring imaging techniques such as PET or SPECT.
XX Ciclo
1978
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7

Ruozi, Giulia. "An in vivo functional selection strategy to identify novel genes sustaining cardiac function." Doctoral thesis, Scuola Normale Superiore, 2012. http://hdl.handle.net/11384/85943.

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Xu, Dan. "Cellular Immunity in Recombinant Adeno-Associated Virus Vector Mediated Gene Therapy." The Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1313504203.

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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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10

Pacouret, Simon. "Thermostability of Adeno-Associated Virus (AAV) Vectors." Thesis, Nantes, 2018. http://www.theses.fr/2018NANT1041/document.

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Les virus adéno-associés (AAVs) sont des virus à ADN simple brin, nonenveloppés, considérés comme des candidats de choix pour la thérapie génique. Pour augmenter les chances de succès des thérapies géniques basées sur l’AAV, des efforts sont actuellement faits pour développer de nouvelles capsides virales, qui seraient plus résistantes à l’immunité préexistante, plus spécifiques de certains tissus, et compatibles avec une production à grande échelle. L’un des défis posés par le développement de nouveaux vecteurs consiste à comprendre comment conférer de nouvelles fonctions biologiques aux capsides d’AAVs, sans compromettre leur intégrité structurale. Pour ce faire, il est nécessaire d’améliorer notre compréhension des mécanismes gouvernant la métastabilité des capsides d’AAVs. L’objectif de cette thèse était d’étudier la thermostabilité des AAVs, ses liens avec leurs propriétés biologiques, ainsi que ses applications dans le domaine du contrôle qualité des préparations d’AAVs recombinants Dans un premier temps, nous étendons les travaux existants à l’étude de virus AAVs ancestraux (AncAAVs), reconstruits in silico. Nous montrons que Anc80, l’ancêtre commun prédit d’AAV1, 2, 8 et 9, est plus thermostable que ses descendants (ΔT = 15-20°C). Nous identifions ensuite, par une analyse de type phénotype-phylogénie, 12 acides aminés jouant potentiellement un rôle important dans la stabilisation des capsides virales. Nous montrons ensuite que la thermostabilité des capsides d’AAVs, mesurée par fluorimétrie différentielle à balayage (DSF), est utile pour déterminer, à l’échelle protéique, l’identité des préparations de vecteurs viraux, une opération requise par les agences réglementaires. Pour finir, nous appliquons ce test d’identité à l’étude de l’homogénéité structurale des librairies d’AAVs. Ces travaux de thèse pourraient s’avérer utiles pour développement et le manufacturing de nouveaux AAVs recombinants pour la thérapie génique
Adeno-associated virus (AAV) vectors have emerged as promising gene delivery vehicles for gene therapy. To improve the probability of success of AAV-based therapeutic strategies, efforts are currently being made to engineer novel capsids able to produce and purify well, escape pre-existing immunity, and target specific cell populations more efficiently. One challenge in AAV vector engineering is to understand how to confer new functions to the viral capsid without altering its structural integrity. To do so, there is a critical need to gain further knowledge on the mechanisms steering AAV capsid metastability. The objective of this thesis is to investigate the thermal stability of AAVs, its impact on AAV biology, and applications to quality control of AAV preparations. First, we extend existing thermal stability studies to in silico reconstructed ancestral AAV particles (AncAAVs), and show that, Anc80, the common putative ancestor of AAV1, 2, 8 and 9, is 15-20°C more thermostable than its contemporary homologs. Using phenotype-tophylogeny mapping, we also identify a set of 12 residues potentially playing a key role in capsid metastability. Second, we demonstrate that capsid thermal stability, as measured by Differential Scanning Fluorimetry (DSF), can be used for identification of AAV preparations at the protein level, a requirement of regulatory agencies. Last, we apply this identity assay to the study of capsid mosaic formation in AAV library preparations. This work will help guide the engineering and manufacturing of improved AAV vectors for gene therapy
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Books on the topic "Adeno-Associated Viral (AAV) vectors"

1

Berns, Kenneth I., and Catherine Giraud, eds. Adeno-Associated Virus (AAV) Vectors in Gene Therapy. Berlin, Heidelberg: Springer Berlin Heidelberg, 1996. http://dx.doi.org/10.1007/978-3-642-80207-2.

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Adeno-Associated Virus (Aav) Vectors in Gene Therapy. Springer-Verlag Telos, 1996.

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Giraud, Catherine, and Kenneth I. Berns. Adeno-Associated Virus (AAV) Vectors in Gene Therapy. Springer London, Limited, 2012.

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Adeno-Associated Viral Vectors for Gene Therapy. Elsevier, 2005. http://dx.doi.org/10.1016/s0075-7535(05)x1016-6.

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Adeno-Associated Virus (Aav): Vectors in Gene Therapy (Current Topics in Microbiology and Immunology). Springer-Verlag, 1996.

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Muzyczka, Nicholas. Viral Expression Vectors (Current Topics in Microbiology and Immunology). Springer, 1992.

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Biloshytsky, Vadym, and Roman Cregg. Pioneering use of gene therapy for pain. Edited by Paul Farquhar-Smith, Pierre Beaulieu, and Sian Jagger. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198834359.003.0083.

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The landmark paper discussed in this chapter is ‘Gene therapy for pain: Results of a Phase I clinical trial’, published by Fink et al. in 2011. In this study, the first of its kind, researchers studied the efficacy and safety of a modified herpes simplex virus (HSV) vector used to deliver PENK, which encodes proenkephalin, which is cleaved into the enkephalin peptides Met-enkephalin and Leu-enkephalin, which induce analgesia by acting on opioid receptors. The development of the HSV vector was based in part on results studies in which adenovirus, adeno-associated virus, or non-viral vectors were used to overexpress genes. Overexpression of a variety of large molecules leads to a reduction in pain-related behaviour in animals. Gene therapy in the treatment of chronic pain seems to offer a promising alternative to systemic or highly invasive therapies. However, additional research is needed to determine the safety, effectiveness, and cost-efficiency of this approach.
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Book chapters on the topic "Adeno-Associated Viral (AAV) vectors"

1

Blessing, Daniel, Nicole Déglon, and Bernard L. Schneider. "Scalable Production and Purification of Adeno-Associated Viral Vectors (AAV)." In Methods in Molecular Biology, 259–74. New York, NY: Springer New York, 2018. http://dx.doi.org/10.1007/978-1-4939-8730-6_17.

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Fakhiri, Julia, Manuela Nickl, and Dirk Grimm. "Rapid and Simple Screening of CRISPR Guide RNAs (gRNAs) in Cultured Cells Using Adeno-Associated Viral (AAV) Vectors." In Methods in Molecular Biology, 111–26. New York, NY: Springer New York, 2019. http://dx.doi.org/10.1007/978-1-4939-9170-9_8.

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Patrício, Maria I., and Robert E. MacLaren. "Retinal Gene Therapy for Choroideremia: In Vitro Testing for Gene Augmentation Using an Adeno-Associated Viral (AAV) Vector." In Retinal Gene Therapy, 89–97. New York, NY: Springer New York, 2017. http://dx.doi.org/10.1007/978-1-4939-7522-8_7.

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Guiner, Caroline Le, Phillipe Moullier, and Valder R. Arruda. "Biodistribution and Shedding of AAV Vectors." In Adeno-Associated Virus, 339–59. Totowa, NJ: Humana Press, 2011. http://dx.doi.org/10.1007/978-1-61779-370-7_15.

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Gray, John T., and Serge Zolotukhin. "Design and Construction of Functional AAV Vectors." In Adeno-Associated Virus, 25–46. Totowa, NJ: Humana Press, 2011. http://dx.doi.org/10.1007/978-1-61779-370-7_2.

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Samulski, Richard Jude. "Adeno-associated Viral Vectors." In Viruses in Human Gene Therapy, 53–76. Dordrecht: Springer Netherlands, 1995. http://dx.doi.org/10.1007/978-94-011-0555-2_3.

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de Backer, Marijke W. A., Keith M. Garner, Mieneke C. M. Luijendijk, and Roger A. H. Adan. "Recombinant Adeno-Associated Viral Vectors." In Methods in Molecular Biology, 357–76. Totowa, NJ: Humana Press, 2011. http://dx.doi.org/10.1007/978-1-61779-310-3_24.

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Hallek, M., C. M. Wendtner, R. Kotin, D. Michl, and E. L. Winnacker. "Recombinant Adeno-Associated Virus (r AAV) Vectors." In Gene Therapy, 73–91. Basel: Birkhäuser Basel, 1999. http://dx.doi.org/10.1007/978-3-0348-7011-5_6.

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Berns, K. I., and C. Giraud. "Biology of Adeno-associated Virus." In Adeno-Associated Virus (AAV) Vectors in Gene Therapy, 1–23. Berlin, Heidelberg: Springer Berlin Heidelberg, 1996. http://dx.doi.org/10.1007/978-3-642-80207-2_1.

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Gao, Guangping, Li Zhong, and Olivier Danos. "Exploiting Natural Diversity of AAV for the Design of Vectors with Novel Properties." In Adeno-Associated Virus, 93–118. Totowa, NJ: Humana Press, 2011. http://dx.doi.org/10.1007/978-1-61779-370-7_4.

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Conference papers on the topic "Adeno-Associated Viral (AAV) vectors"

1

Dombrowski, T., A. Dieter, V. Rankovic, M. Jeschke, and T. Moser. "Optogenetic modification of the auditory nerve with adeno-associated viral vectors." In Abstract- und Posterband – 89. Jahresversammlung der Deutschen Gesellschaft für HNO-Heilkunde, Kopf- und Hals-Chirurgie e.V., Bonn – Forschung heute – Zukunft morgen. Georg Thieme Verlag KG, 2018. http://dx.doi.org/10.1055/s-0038-1640292.

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Jheel, Pandya, Kellee Britt, and George Aslanidi. "Abstract 714: Bioengineering of the adeno-associated virus (AAV) vectors for dendritic cell (DC)-based immunotherapy." In Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.am2014-714.

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Sharma, Satish K., Blerina Ducka, Imre G. Redai, Zhilong Jiang, Akshit R. Gupta, Cynthia Koziol-White, Ru Xiao, James Wilson, Maria Limberis, and Angela Haczku. "Adeno-Associated Viral (AAV)-Surfactant Protein D (SP-D)-Gene Treatment Rescued The Pulmonary Innate Immune Cell Abnormalities In SP-D-/- Mice." In American Thoracic Society 2012 International Conference, May 18-23, 2012 • San Francisco, California. American Thoracic Society, 2012. http://dx.doi.org/10.1164/ajrccm-conference.2012.185.1_meetingabstracts.a1057.

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