SPECIFIC AIMS: The hypothesis underlying all of these studies is that a full understanding of their pharmacokinetic and pharmacodynamic properties of gene transfer vectors will be required for the eventual development of tissue- and cell-specific vector targeting for precise and effective gene delivery. These studies are therefore intended to characterize the fate and effects of gene transfer into mice and a non- human primate and into the mouse and primate fetus and to characterize the host response to the genetic modification.
The specific aims of the studies are: 1. to characterize the distribution and pharmacological properties, transgene expression and cellular effects of VSV-G-pseudotyped retrovirus and lentivirus vectors following systematic introduction into mice and macaques and into mouse and non-macaque fetuses. 2. to characterize mechanisms of initial vector interaction with cell surface receptors, with special attention to the role of primary attachment molecules such as glycosaminoglycans and selectins. 3. to determine the nature and extent of the host immune response to the vectors and their expressed transgenes; 4. to test the effects of in vivo expression of an antibody specific for the extra-cellular LDL of atherosclerotic lesions. 5. to characterize delivery of phage display peptide libraries to mouse and macaque fetuses and use in vivo phage panning methods to identify peptides that home to fetal tissues in vivo.
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