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Design of artificial viruses by combinatorial protein engineering


The specific delivery of therapeutic genes to defined target cell populations is a major challenge in gene therapy. This requires a sophisticated vector that is able to protect the DNA from degradation, interact specifically with cell surface receptors on target cells, cross the cell membrane and allow nuclear import of the exogenous DNA. Viral vectors are very efficient in depositing exogenous DNA into cells, but safety issues, lack of cell specificity, limited DNA packaging capacity and costs of large-sca le production hamper the general use of viral vectors for gene therapeutic application. Here, we propose to design "artificial viruses" that are as efficient as viral vectors in gene delivery but are safe to use, cell-type specific and can be cost-effectiv ely produced at large scale. These artificial viruses will be designed to utilize the cellular entry mechanism of bacterial protein toxins to deliver DNA into target cells. A "survival of the fittest" approach will be used to select for artificial viruses most capable of transfecting plasmid DNA into mammalian cells from a large DNA library encoding for many different artificial viruses. This will be achieved by generating libraries of hybrid genes that combine the cell surface receptor-binding domain and t ranslocation domain of several bacterial toxins with the DNA-binding domain and nuclear localization signal of several transcription factors. Single members of the hybrid gene libraries will be transcribed and translated inside micron-sized aqueous droplet s of a water-in-oil emulsion (the artificial cells). Multiple copies of identical chimeric proteins that are properly folded will self-assemble into an artificial virus inside the artificial cell by interaction of the DNA-binding domain of the chimeric pro teins with the plasmid DNA. This creates a physical linkage between genotype (plasmid DNA) and phenotype (chimeric protein). After isolation of the artificial viruses #

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