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Non-viral gene therapy using a cell-targeted ternary vector.
In a major interdisciplinary research project, we are elucidating the structure and mode of action of a novel, highly potent non-viral gene delivery system, and designing new non-viral gene delivery vectors based on this system. The work is being carried out in collaboration with Dr S. L Hart (Institute of Child Health, UCL), Dr H C Hailes (Chemistry), Professor M J Lawrence (School of Pharmacy, KCL), and Dr D Zicha (ICRF). These targeted, self-assembling lipid:peptide (lipopolyplex) vector complexes (LID) consist of a lipid component, Lipofectin (L) (the cationic lipid DOTMA with a co-lipid DOPE in a 1:1 ratio), plasmid DNA (D), and a dual-function, cationic peptide component (I) comprising both a K 16 (DNA condensation) and a cell-targeting sequence. LID systems display high transfection efficiency and low toxicity in vitro and in vivo , transfect non-dividing cells efficiently, and are well tolerated with low immunogenicity in vivo . Our working hypothesis for the transfection pathway is that the LID complexes bind to specific integrins on the cell surface and are internalised by receptor-mediated endocytosis. The lipid component then mediates endosomal fusion, releasing the peptide/DNA complex into the cytoplasm: the peptide then mediates transport into the nucleus, followed by transcription. Using fluorescently labelled vector components, and biophysical techniques (FCS, FRET, fluorescence quenching and cryo-EM), we have worked out the macromolecular organisation of the three components (peptide, lipid and DNA) within the vector.This is the first time that a nanostructure of this complexity has been analysed in this detail. We are synthesising new peptide, lipid and lipopeptide structures in order to improve the efficiency and stability of this vector. The rationale behind much of the design is to understand and imitate those features of viruses that make them such efficient gene transfer agents - e.g. superior serum stability, cell-specific targeting and receptor-mediated endocytosis, enhanced transport of the internalised DNA to the nucleus. For each enhancement of each component, we are carrying out systematic studies of the biophysics, intracellular transport and cell-specific transfection properties of the resulting complex in order to understand and precisely define the effects that structural changes to each component has on the activity of the vector.
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