14 - March 5, 2013.docx

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Laboratory Medicine and Pathobiology
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March 5, 2013 Actual gene therapy – use a gene as a therapeutic in genetic disease or acquired genetic disease Introducing gene into somatic cells for treatment Correct the gene – directing therapy at the ROOT cause Duration of effect – for genetic disease, long-term effect No other conventional treatment To achieve gene transfer – generally, two roots – one is the idea of ex vivo gene therapy; other is in vivo In vivo – directly insert the gene into the individual; hope that approach gets to the right kinds of cells - Good idea, difficult to accomplish Ex vivo gene therapy – good delivery vehicle – ex. Exploit viruses Target gene has optimal gene expression – What is best target cell? Turnover – best target are stem cells, that can give rise to multiple other cells Do not take tissue samples repeatedly from patient – not desired These issues apply to all types of gene therapy, all strategies Most used method of delivery – type of viral vector – multiple kinds – idea is that vector takes advantage of the very efficient gene transfer that tends to happen with viral infection – Oncoretroviral vectors – viruses that are RNA viruses – to get DNA, transfer RNA into DNA, using reverse transcriptase – Adenovirus – turn down gene expression – so gives short term expression; DNA does not integrate (good thing) but limited term of effect Adenoviruses – large viruses – produce lots of proteins – unwanted immune responses are concerns Gutless vectors – less immunogenic – large payload – Adeno-associated virus vectors – element of safety Herpes simplex – can infect central nervous system – establish latent infection – interest property – have good insert capacity – do not integrate – some notable ability for long-term expression Lentivirus – Integration is an issue if the integrated virus does not stay put; they may be able to move about, using transposition machinery of the cell Nonviral vectors Developed primarily to get around concern of immune response of individuals – Receptor-mediated endocytosis – DNA coupled to targeting molecule, which can bind to cell receptor so cell may uptake the DNA Direct injection – gene gun technique – may get local injury – Liposome – smallest representation of what can fuse with the cell membrane – synthetic lipid bilayer that is cell compatible – stimulate to fuse with membrane – variety of liposome that bind negatively charged DNA, package nicely around DNA – fairly easily can get into cells – simply because have property that is similar to cell membrane – calcium, stress, to allow lipids to fuse – quite effective Liposomes work best for liver gene therapry, but not as effective for other organs Liposomes – artificial viruses – Rationale for gene therapy approach Recessive – more than 50% loss of gene product Dominant – haplosufficient – boost with more Nature of mutation and disease features Approaches to gene therapy – take particular gene – put in disease cell – increase in gene product – for recessive disease, where there is loss of function Variations on idea of adding gene and giving function – ex, treatment for cancer – Add to disease cell that is toxic – gives off toxin that causes cells to die – toxic genes Or, add prodrug metabolizing gene – can metabolize product that once you add it – some control about so control toxicity – one such
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