FUSIGENIC VIRAL LIPOSOME FOR GENE-THERAPY IN CARDIOVASCULAR-DISEASES

To improve the efficiency of liposome-mediated DNA transfer as a tool for gene therapy, we have developed a fusigenic liposome vector based on principles of viral cell fusion. The fusion proteins of hemagglutin ating virus of Japan (HVJ; also Sendai virus) are complexed with lipos omes that encapsulate oligodeoxynucleotide or plasmid DNA. Subsequent fusion of HVJ-liposomes with plasma membranes introduces the DNA direc tly into the cytoplasm. In addition, a DNA-binding nuclear protein is incorporated into the HVJ-liposome particle to enhance plasmid transge ne expression. The fusigenic viral liposome vector has proven to be ef ficient for the intracellular introduction of oligodeoxynucleotide, as well as intact genes up to 100 kbp, both in vitro and in vivo. Many a nimal tissues have been found to be suitable targets for fusigenic vir al liposome DNA transfer. In the cardiovascular system, we have docume nted successful cytostatic gene therapy in models of vascular prolifer ative disease using antisense oligodeoxynucleotides against cell cycle genes, double-stranded oligodeoxynucleotides as ''decoys'' to trap th e transcription factor E2F, and expression of a transgene encoding the constitutive endothelial cell form of nitric oxide synthase. Similar strategies are also effective for the genetic engineering of vein graf ts and for the treatment of a mouse model of immune-mediated glomerula r disease.