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• W2944627180 abstract "Author(s): Santiago Ortiz, Jorge Luis | Advisor(s): Schaffer, David V | Abstract: Gene therapy – the introduction of genetic material into cells and tissues of interest for a therapeutic purpose – has emerged as a very promising treatment for many diseases. Recent advances in genomics and proteomics, coupled with the advent of genome editing technologies, have generated an immense pool of potential nucleic acid cargoes that could be delivered as therapies for a wide array of diseases, ranging from monogenic disorders to cancer. However, before such therapies can be successful, a major hurdle must be overcome: the development of gene-carrying vehicles – also referred to as vectors – that can safely, efficiently, and specifically deliver those therapeutic payloads to the desired cells. The goal of this dissertation was therefore to address a major need in the field: the development of improved gene delivery vectors. To date, more than 2,000 clinical trials employing gene transfer have taken place, establishing the safety of a number of vectors. Non-viral vectors can be easily produced at a large-scale and are amenable to the engineering of their chemical and physical properties via chemical modifications, but they suffer from a low delivery efficiency and cell toxicity. On the other hand, viral vectors harness the highly evolved mechanisms that viruses have developed to efficiently recognize and infect cells and offer several advantages that make them suitable candidates for use in gene delivery, both for therapeutic application and as tools for biological studies. In fact, gene therapy has enjoyed increasing success in clinical trials for numerous disease targets in large part due to the gene delivery capabilities viral vectors. Vectors derived from viruses have been used in the majority (over 68%) of gene therapy clinical trials to date, and the most frequently used have been based on adenovirus, retrovirus, vaccinia virus, herpesvirus, and adeno-associated virus (AAV). AAV vectors are non-pathogenic and can transduce numerous dividing and non-dividing cell types. Because of these characteristics, AAV vectors have been utilized for gene therapy in various tissues. The amino acid composition of the viral capsid affects tropism (tissue specificity), cell receptor usage, and susceptibility to anti-AAV neutralizing antibodies – properties that influence efficacy in therapeutic gene delivery. However, AAV vectors can still encounter formidable impediments to efficacious gene delivery, including poor transduction (infection and expression of delivered gene) of some cell types, off-target transduction, difficulties with biological transport barriers, and potential risks associated with the integration of their genetic load. Extensive engineering of the AAV capsid promises to overcome these delivery challenges and improve numerous clinically relevant properties. To this end, the overarching goal of my work in the Schaffer Laboratory, which is presented in this thesis dissertation, was to advance current gene delivery methods through the engineering and characterization of novel adeno-associated virus vectors for gene therapy and research applications. To access new viral capsid sequences with potentially enhanced infectious properties and to gain insights into AAV’s evolutionary history, we computationally designed and experimentally constructed an ancestral AAV capsid library. We performed selection for infectivity on the library, studied the resulting amino acid distribution, and characterized the selected variants, which yielded viral particles that were broadly infectious across multiple cell types. Ancestral variants displayed higher thermostability than modern (extant) natural AAV serotypes, a property that makes them promising templates for protein engineering applications, including directed evolution. Additionally, some variants displayed high in vivo infectivity on a mouse model, highlighting their potential for gene therapy. Motivated by the success of directed evolution in the engineering of proteins with novel or enhanced properties, I worked in the engineering of AAV vectors for gene delivery to glioblastoma multiforme (GBM), a highly aggressive type of brain cancer. For this, I conducted directed evolution to select AAV variants with selective localization to and infectivity on GBM tumor cells and tumor initiating cells (TICs). Using an accurate GBM mouse model, I performed in vitro and in vivo selection, recovering viral particles that successfully trafficked to tumor cells and TICs in the brain after systemic administration to tumor-bearing animals. Following three rounds of in vivo selection, convergence was achieved upon several variants, the most abundant of which emerged from the ancestral reconstruction library. The selected variants are currently being characterized and assessed for their ability to deliver reporter and therapeutic genes, hopefully resulting in improved suppression of tumor progression compared to delivery with existing AAV serotypes. These novel vectors could enable new, potent therapies to treat GBM tumors and pave the way for engineering AAV vectors for other cancer targets.In summary, this dissertation presents work on the development and characterization of a novel AAV capsid library, as well as on the implementation of this and of other libraries towards the engineering of novel AAV variants with selective gene delivery properties for brain tumors. The work herein presented aims to advance both the field of AAV vector engineering as a whole and the specific application of AAV vectors towards next generation cancer therapies." @default.
• W2944627180 created "2019-05-16" @default.
• W2944627180 creator A5081125252 @default.
• W2944627180 creator A5082957489 @default.
• W2944627180 date "2016-01-01" @default.
• W2944627180 modified "2023-09-23" @default.
• W2944627180 title "Engineering of Novel Adeno-Associated Virus Vectors for Gene Therapy Applications" @default.
• W2944627180 cites W1515021808 @default.
• W2944627180 cites W1533611994 @default.
• W2944627180 cites W1594355808 @default.
• W2944627180 cites W1598925812 @default.
• W2944627180 cites W1684140257 @default.
• W2944627180 cites W1787923008 @default.
• W2944627180 cites W1965727113 @default.
• W2944627180 cites W1970942128 @default.
• W2944627180 cites W1975795497 @default.
• W2944627180 cites W1977643218 @default.
• W2944627180 cites W1982913141 @default.
• W2944627180 cites W1984483719 @default.
• W2944627180 cites W1988706862 @default.
• W2944627180 cites W1990785174 @default.
• W2944627180 cites W1994901446 @default.
• W2944627180 cites W2001544973 @default.
• W2944627180 cites W2004332713 @default.
• W2944627180 cites W2012530297 @default.
• W2944627180 cites W2014018936 @default.
• W2944627180 cites W2015445474 @default.
• W2944627180 cites W2018671779 @default.
• W2944627180 cites W2019519191 @default.
• W2944627180 cites W2021575109 @default.
• W2944627180 cites W2023962213 @default.
• W2944627180 cites W2025016054 @default.
• W2944627180 cites W2025725192 @default.
• W2944627180 cites W2025830548 @default.
• W2944627180 cites W2028074588 @default.
• W2944627180 cites W2030074887 @default.
• W2944627180 cites W2033689077 @default.
• W2944627180 cites W2035833975 @default.
• W2944627180 cites W2039233803 @default.
• W2944627180 cites W2043828994 @default.
• W2944627180 cites W2044005085 @default.
• W2944627180 cites W2046329059 @default.
• W2944627180 cites W2048281866 @default.
• W2944627180 cites W2051052420 @default.
• W2944627180 cites W2053654862 @default.
• W2944627180 cites W2053670662 @default.
• W2944627180 cites W2053862817 @default.
• W2944627180 cites W2058923118 @default.
• W2944627180 cites W2059193290 @default.
• W2944627180 cites W2060551076 @default.
• W2944627180 cites W2064668202 @default.
• W2944627180 cites W2064702460 @default.
• W2944627180 cites W2067074806 @default.
• W2944627180 cites W2068303118 @default.
• W2944627180 cites W2070119976 @default.
• W2944627180 cites W2074713417 @default.
• W2944627180 cites W2082409875 @default.
• W2944627180 cites W2088369745 @default.
• W2944627180 cites W2090760184 @default.
• W2944627180 cites W2096287682 @default.
• W2944627180 cites W2096753000 @default.
• W2944627180 cites W2101330172 @default.
• W2944627180 cites W2101653483 @default.
• W2944627180 cites W2102111681 @default.
• W2944627180 cites W2103037531 @default.
• W2944627180 cites W2103803304 @default.
• W2944627180 cites W2104137149 @default.
• W2944627180 cites W2115734610 @default.
• W2944627180 cites W2117029319 @default.
• W2944627180 cites W2117491517 @default.
• W2944627180 cites W2118265845 @default.
• W2944627180 cites W2122304523 @default.
• W2944627180 cites W2126115955 @default.
• W2944627180 cites W2128659329 @default.
• W2944627180 cites W2128683756 @default.
• W2944627180 cites W2133171074 @default.
• W2944627180 cites W2139104080 @default.
• W2944627180 cites W2139983345 @default.
• W2944627180 cites W2145127625 @default.
• W2944627180 cites W2146855795 @default.
• W2944627180 cites W2152853777 @default.
• W2944627180 cites W2154772938 @default.
• W2944627180 cites W2159726820 @default.
• W2944627180 cites W2160382843 @default.
• W2944627180 cites W2160986529 @default.
• W2944627180 cites W2163424680 @default.
• W2944627180 cites W2163859522 @default.
• W2944627180 cites W2166739815 @default.
• W2944627180 cites W2170160409 @default.
• W2944627180 cites W2233607944 @default.
• W2944627180 cites W2266837556 @default.
• W2944627180 cites W2317196257 @default.
• W2944627180 cites W2396345563 @default.
• W2944627180 cites W39050333 @default.
• W2944627180 cites W866037220 @default.
• W2944627180 cites W2528806349 @default.
• W2944627180 hasPublicationYear "2016" @default.
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