Abstract: Disclosed herein are methods for introducing functional mitochondria into liver cells in living animals (e.g., mammals). The disclosed compositions and methods can be used to treat clinical conditions characterized by genetic or acquired mitochondrial defects and the resulting dysfunctions and diseases therefrom.

Abstract: The present disclosure relates to, inter alia, compositions and kits comprising an asialoglycoprotein covalently attached to a polycation, and functional mammalian mitochondria that are at least partially purified and are electrostatically bound to the AsG-polycation molecule; as well as methods of their preparation and use.

Abstract: The present disclosure relates to, inter alia, compositions and kits comprising an asialoglycoprotein covalently attached to a polycation, and functional mammalian mitochondria that are at least partially purified and are electrostatically bound to the AsG-polycation molecule; as well as methods of their preparation and use.

Abstract: Compositions and methods for the inhibition of viral replication are provided. In some embodiments, the compositions include a nucleic acid sequence that is identical to a region of the hepatitis C virus (HCV) genome. In other embodiments, the compositions may include a nucleic acid sequence that has at least about 45% to about 95% sequence identity to the native HCV sequence and that has a similar secondary and tertiary structure to the native HCV sequence. In other embodiments, the compositions may include a nucleic acid sequence that does not have significant sequence identity to the native HCV sequence and that has a similar secondary and tertiary structure to the native HCV sequence. Also provided are methods for the treatment of a patient having an HCV infection by administering one of the compositions described herein, and uses of the compositions described herein in the manufacture of a medicament for the inhibition of HCV replication.

Abstract: The present invention relates to the preparation of non-human animals having chimeric livers, whereby some or substantially all of the hepatocytes present are human hepatocytes. It is based, at least in part, on the discovery that rats, tolerized in utero against human hepatocytes, were found to serve as long-term hosts for human hepatocytes introduced post-natally, and the introduced hepatocytes maintained their differentiated phenotype, as evidenced by continued production of human albumin. The present invention further relates to the use of such animals as models of various liver diseases, including viral invention. Such embodiments are based on the discovery that transplanted human hepatocytes in chimeric livers were found to be susceptible to Hepatitis B virus and Hepatitis C virus infection.

Abstract: Molecular complexes for targeting a gene encoding a secretory protein to a specific cell in vivo and obtaining secretion of the protein by the targeted cell are disclosed. An expressible gene encoding a desired secretory protein is complexed to a conjugate of a cell-specific binding agent and a gene-binding agent. The cell-specific binding agent is specific for a cellular surface structure which mediates internalization of ligands by endocytosis. An example is the asialoglycoprotein receptor of hepatocytes. The gene-binding agent is a compound such as a polycation which stably complexes the gene under extracellular conditions and releases the gene under intracellular conditions so that it can function within a cell. The molecular complex is stable and soluble in physiological fluids and can be used in gene therapy to selectively transfect cells in vivo to provide for production and secretion of a desired secretory protein.

Abstract: The present invention relates to the preparation of non-human animals having chimeric livers, whereby some or substantially all of the hepatocytes present are human hepatocytes. It is based, at least in part, on the discovery that rats, tolerized in utero against human hepatocytes, were found to serve as long-term hosts for human hepatocytes introduced post-natally, and the introduced hepatocytes maintained their differentiated phenotype, as evidenced by continued production of human albumin.

Abstract: The present invention relates to the preparation of non-human animals having chimeric livers, whereby some or substantially all of the hepatocytes present are human hepatocytes. It is based, at least in part, on the discovery that rats, tolerized in utero against human hepatocytes, were found to serve as long-term hosts for human hepatocytes introduced post-natally, and the introduced hepatocytes maintained their differentiated phenotype, as evidenced by continued production of human albumin.

Abstract: The present invention relates to the preparation of non-human animals having chimeric livers, whereby some or substantially all of the hepatocytes present are human hepatocytes. It is based, at least in part, on the discovery that rats, tolerized in utero against human hepatocytes, were found to serve as long-term hosts for human hepatocytes introduced post-natally, and the introduced hepatocytes maintained their differentiated phenotype, as evidenced by continued production of human albumin. The present invention further relates to the use of such animals as models of various liver diseases, including viral invention. Such embodiments are based on the discovery that transplanted human hepatocytes in chimeric livers were found to be susceptible to Hepatitis B virus and Hepatitis C virus infection.

Abstract: Molecular complexes for targeting oligonucleotides, such as antisense oligonucleotides or ribozymes, to a specific cell to block expression of a gene or genes in the cell are described. The single-stranded poly- or oligonucleotide is complexed to a conjugate of a cell-specific binding agent and a poly- or oligonucleotide-binding agent. The cell-specific binding agent is specific for a cellular surface structure which mediates internalization of the complex. An example is the asialoglycoprotein receptor of hepatocytes. The poly- or oligodeoxy-nucleotide-binding agent is a compound such as a polycationic protein which stably complexes the oligonucleotide under extracellular conditions and releases it under intracellular conditions so that it can hybridize with the target RNA.

Abstract: A targetable gene delivery system is provided for introducing foreign genes into mamallian cells. The system employs a soluble targetable DNA complex and utilizes receptor-mediated endocytosis to endow cell specificity. The soluble DNA-carrying complex is formed by non-covalently binding a ligand conjugate with the foreign gene. The conjugate, in turn, is formed by bonding receptor-specific ligands such as asialoglycoproteins to polycations such as polylysine through covalent bonds such as disulfide bonds. The system exhibits a high degree of cell specificity and offers potential for the treatment of inherited genetic disorders.

Abstract: An improved soluble molecular complex for targeting a polynucleotide to a specific cell is disclosed. The molecular complex comprises (a) a polynucleotide (b) a carrier made up of a polynucleotide binding agent and a cell-specific binding agent which binds to a surface molecule of the cell and is internalized into an endosome, and (c) a bacterial component or fragment thereof which lyses the endosome and causes the polynucleotide to be released into the cytoplasm of the cell. In a preferred embodiment of the invention the polynucleotide binding agent is polylysine, the cell-specific binding agent is an asialoglycoprotein, and the bacterial component is listeriolysin O. The disclosed soluble molecular complex and methods of use can be used therapeutically to deliver genes and antisense polynucleotides to specific cells in vivo.

Abstract: The expression of polynucleotide introduced into a cell by means of a targeted complex of the polynucleotide linked to a cell-specific binding agent can be enhanced and prolonged by inhibiting translocation or fusion of endosomes to lysosomes using colchicine.

Abstract: A targetable gene delivery system is provided for introducing foreign genes into mammalian cells. The system employs a soluble targetable DNA complex and utilizes receptor-mediated endocytosis to endow cell specificity. The soluble DNA-carrying complex is formed by non-covalently binding a ligand conjugate with the foreign gene. The conjugate, in turn, is formed by bonding receptor-specific ligands such as asialoglycoproteins to polycations such as polylysine through covalent bonds such as disulfide bonds. The system exhibits a high degree of cell specificity and offers potential for the treatment of inherited genetic disorders.

Abstract: A targetable gene delivery system is provided for introducing foreign genes into mammalian cells. The system employs a soluble targetable DNA complex and utilizes receptor-mediated endocytosis to endow cell specificity. The soluble DNA-carrying complex is formed by non-covalently binding a ligand conjugate with the foreign gene. The conjugate, in turn, is formed by bonding receptor-specific ligands such as asialoglycoproteins to polycations such as polylysine through covalent bonds such as disulfide bonds. The system exhibits a high degree of cell specificity and offers potential for the treatment of inherited genetic disorders.