Exploiting Viruses as Gene Therapy & Vaccine Vectors
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| Gene Therapy | Introduction of DNA sequences into the cell of a patient with the aim of achieving a clinical benefit (fix something that is wrong)
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| Gene Therapy in CA | Does not aim to restore normal function, the objective is to kill the CA cells
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| Uses of Eukaryotic Virus Vectors | Gene Therapy, Recombinant vaccines, Anticancer agents
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| Most common diseases addressed by gene therapy clinical trials | Cancer, vascular, & Monogenic diseases
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| Most common gene types transferred in gene therapy clinical trials | Cytokine, Antigen, Tumor suppressor
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| Most common vectors used in gene therapy clinical trials | Adenovirus, Retrovirus, Naked/Plasmid DNA
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| 2 Types of Gene Therapy | 1. Somatic cell gene therapy -- 2.Germ line gene therapy
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| 2 Methods of Delivery | IN VIVO therapy: patient is injected with the modified gene therapy vector -- & -- EX VIVO therapy: cells are removed, genes introduced, cells transplanted back into patient
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| Chemical/Physical Methods of DNA Delivery Systems | Electroporation, Calcium Phophatases, Liposomes, Naked DNA gene gun
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| Liposomes | Gold labeled DNA complexed with lipid, taken up via endocytic process
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| liposomes advantage | works great in vivo because high production & effects dividing and non-dividng cells
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| liposomes disadvantage | plasmid liposome complex vector cant specifically target a cell, less efficient, requires large amounts to acheive gene transfer
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| Why use Viruses for Gene Therapy? | Experts at delivering genetic info to cells, we can Construct viruses for gene delivery, & different viruses target different tissues
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| 2 ways to prevent virus vectors from causing disease | 1.Engineer a non-pathogenic virus that expresses therapeutic gene -- 2.Engineer virus that requires a helper virus to replicate
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| Technical Concerns | Regenerate a replication competent recombinant; Loss of therapeutic gene expression; Inadvertently transferring a contaminating gene or genes along with the therapeutic ones
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| Technical Concerns: Loss of therapeutic gene expression | Many viruses limit gene expression to avoid the immune system. This can be avoided by using an inducible promotor.
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| Gene therapy is difficult in differentiated/non-dividing cells | Many viruses only infect dividing cells. Avoid this by using retrovirus vectors that encode HIV integrase, which allows them to effectively infect nondividing cells
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| Most popular Viral Vectors | Adenoviruses, Adeno-associated virus, Retroviruses, HSV, & Vaccinia
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| Adenovirus Vectors | Infect dividing & nondividing cells. E1 is replaced with gene of interest. No integration. Severe risk of immune response
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| AAV Vectors | non-pathogenic, infects dividing & nondiving cells, always integrates into chromosome 19, long term expression. BUT very small
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| Retroviral Vectors | long term expression, can be pakaged with G protein of VSV so can infect many cell types, less immunogenic than adenovirus, integrates genome
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| HSV Vectors | potential for nuerologic delivery, accepts large inserts, easy to manipulate, episomal latent infection can lead to long-term expression
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| HSV & B-gal | B-gal replaces an essential immediate-early gene (replication deficient virus); HSV delivers B-gal reporter gene to neurons; can visually check for infection (blue)
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| Vaccinia Virus Vectors | Virus replicates in cytoplasm, so low efficincy of passage of gene into nucleus
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| Virotherpay | a therapy that seeks to harness the natural properties of viruses to aid in the fight against cancer
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| Oncolytic Strategies | Virus surface altered so binds to CA cells only; virus is "armed" with extra genes to enhance effect; virus altered so can replicate in CA cells only
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| Potential Oncolytic Viruses | Reovirus, Adenovirus, VSV, HSV, Vaccinia
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| Adenovirall Vector CA Therapy | Find surface protein specific to CA
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| Viruses, IFN, & CA Therapy | Many CA cells lack functional IFN rsponse, so more susceptible to some viruses. Would stay local & not infect other good tissues that have IFN response
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