Gene therapy is a form of medicine which can have a major impact on human health in this century. The scope of gene therapy ranges from correcting a myriad of genetic diseases to acquired diseases like cancer, neurodegeneration, and infectious diseases. The concept of gene therapy is disarmingly simple-introduce the gene, and its product should alleviate the defect, slow down progression of the disease, or ameliorate the disease. Why then has gene therapy not been proven to be a greater success and the answer lies in the execution of the concept of gene therapy? How do you introduce genes in the liver with a billion cells or the brain with a trillion neurons? Much of the effort, not surprisingly in the field of gene therapy, has remained in generating suitable delivery vehicles. We propose to improve lentivectors based delivery system by utilizing more efficient tissue-specific transcriptional units, which can be regulated by external manipulation. Because viruses are usually foreign to the body, we want to identify the cellular factors that may hinder the production or transduction by delivery vehicles. Since lentiviral vectors have the ability to efficiently introduce foreign genes in fertilized mouse eggs, we plan to use this property to generate mouse disease models, which will mimic the human disease. We specifically want to generate mouse models, which faithfully recapitulate human hemophilia due to factor IX and factor VIII deficiency. The methodology also allows us to explore the possibility to generate transgenic nonhuman primates. We also propose to use the emerging RNA interference technology (SiRNA) for combination with lentiviral vectors to generate recombinant viruses capable of silencing gene expression in cells, tissues and whole organisms. Finally ability of lentiviral vectors to efficiently introduce genes in mouse or human embryonic stem (ES) cells will allow us to manipulate their differentiations to desired lineages. We strongly believe that continued improvement of lentiviral vectors for gene transfer is an important and challenging goal to pursue.
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