73 research outputs found

    INDUCTION OF TOLERANCE BY ORAL ADMINISTRATION OF FACTOR VIII AND TREATMENT OF HEMOPHILA

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    Disclosed herein is a simple method for the treatment of antigen-deficiency diseases, by orally administering to a Subject a therapeutically effective amount of the deficient anti gen, wherein the antigen is not present in a liposome. In one embodiment, the method increases hemostasis in a subject having hemophilia A or B, by orally administering to the hemophiliac atherapeutically effective amount of the appropriate clotting factor other than in a liposome, Sufficient to induce oral tolerance and Supply exogenous clotting factor to the subject

    ORAL TREATMENT OF HEMOPHILIA

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    Disclosed herein is a simple method for the treatment of antigen-deficiency diseases, by orally administering to a subject a therapeutically effective amount of the deficient antigen, wherein the antigen is not present in a liposome. In one embodiment, the method increases hemostasis in a subject having hemophilia A or B, by orally administering to the hemophiliac a therapeutically effective amount of the appropriate clotting factor other than in a liposome, sufficient to induce oral tolerance and supply exogenous clotting factor to the subject

    Expression of active human factor IX in mammary tissue and of milk non human transgenic mammals

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    Recombinant Factor IX characterized by a high percentage of active protein can be obtained in the milk of transgenic animals that incorporate chimeric DNA molecules according to the present invention. Transgenic animals of the present invention are produced by introducing into developing embryos DNA that encodes Factor IX, such that the foreign DNA is stably incorporated in the DNA of germ line cells of the mature animal. Particularly efficient expression was accomplished using a chimeric construct comprising a mammary gland specific promoter, Factor IX cDNA that lacked the complete or any portion of the 5\u27-untranslated and 3\u27-untranslated region, which is substituted with a 5\u27- and 3\u27-end of the mouse whey acidic protein gene. In vitro cell cultures of cells explanted from the transgenic mammal of the invention and methods of producing Factor IX from such said culture and methods of treating hemophilia B are also described

    PRODUCTION OF HIGH LEVELS OF TRANSGENC FACTOR IX WITHOUT GENE RESCUE, AND ITS THERAPEUTIC USES

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    A non-human transgenic mammalian animal, as described above, contains an exogenous double stranded DNA sequence stably integrated into the genome of the animal, which comprises cis-acting regulatory units operably linked to a DNA sequence encoding human FIX protein without the benefit of the presence of a complete milk gene sequence for gene rescue, and a signal sequence is active in directing newly expressed Factor IX into the milk of the animal at levels in an unactivated form that is suitable for Subsequent processing for therapeutic applications in treating Hemophilia B. The transgenic mammals are preferably pigs, cows, sheep, goats and rabbits. The applications include milk derivatives for oral delivery and oral tolerization in the treatment of Hemophilia B

    TREATMENT OF HEMOPHILIA WITH HUMAN FACTORIX PRODUCED IN MAMIMARY TISSUE OF TRANSGENIC MAMMALS

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    Recombinant Factor IX characterized by a high percentage of active protein can be obtained in the milk of transgenic animals that incorporate chimeric DNA molecules according to the present invention. Transgenic animals of the present invention are produced by introducing into developing embryos DNA that encodes Factor IX, such that the foreign DNA is stably incorporated in the DNA of germ line cells of the mature animal. Particularly efficient expression was accomplished using a chimeric construct comprising a mammary gland specific promoter, Factor IX cDNA that lacked the complete or any portion of the 5\u27-untranslated and 3\u27-un-translated region, which is substituted with a 5- and 3\u27-end of the mouse whey acidic protein gene. In vitro cell cultures of cells explanted from the transgenic mammal of the invention and methods of producing Factor IX from such said culture and methods of treating hemophilia B are also described

    TRANSGENIC NONHUMAN MAMMALS PRODUCING FIBRINOGEN IN MILKAND METHODS OF PRODUCING FIBRIN

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    A transgenic, non-human mammalian animal is capable of expressing a heterologous gene for human or other recombinant physiologically functional fibrinogen holoprotein or individual subunit chain polypeptides thereofora modified or fusion fibrinogen in mammary glands of the animals and secreting the expressed product into a body fluid. Methodol ogy employing such a mammal yields recombinant physiologically functional fibrinogens, subunit chain polypeptides thereof, and modified or fusion fibrinogens

    EXPRESSION OF HUMAN PROTEIN C IN MAMMARY TISSUE OF TRANSGENIC MAMMALS

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    Recombinant protein C characterized by a high percentage of active protein can be obtained in the milk of transgenic mammals that incorporate DNAs according to the present invention. Transgenic mammals of the present invention are produced by introducing into developing embryos DNA that encodes protein C, such that the DNA is stably incorporated in the DNA of germ line cells of the mature mammals and inherited in normal, mendelian fashion

    ORAL TREATMENT OF HEMOPHILIA

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    Disclosed herein is a simple method for the treatment of antigen-deficiency diseases, by orally administering to a subject a therapeutically effective amount of the deficient antigen, wherein the antigen is not present in a liposome. In one embodiment, the method increases hemostasis in a subject having hemophilia A or B, by orally administering to the hemophiliac a therapeutically effective amount of the appropriate clotting factor other than in a liposome, sufficient to induce oral tolerance and supply exogenous clotting factor to the subject

    Analysis of the N-glycans of recombinant human Factor IX purified from transgenic pig milk

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    Glycosylation of recombinant proteins is of particular importance because it can play significant roles in the clinical properties of the glycoprotein. In this work, the N-glycan structures of recombinant human Factor IX (tg- FIX) produced in the transgenic pig mammary gland were determined. Themajority of theN-glycans of transgenic pigderived Factor IX (tg-FIX) are complex, bi-antennary with one or two terminal N-acetylneuraminic acid (Neu5Ac) moieties. We also found that the N-glycan structures of tg-FIX produced in the porcine mammary epithelial cells differed with respect to N-glycans from glycoproteins produced in other porcine tissues. tg-FIX contains no detectableNeu5Gc, the sialic acid commonly found in porcine glycoproteins produced in other tissues.Additionally,wewere unable to detect glycans in tg-FIX that have a terminal Galα(1,3)Gal disaccharide sequence, which is strongly antigenic in humans. The N-glycan structures of tg-FIX are also compared to the publishedN-glycan structures of recombinant human glycoproteins produced in other transgenic animal species.While tg-FIX contains only complex structures, antithrombin III (goat), C1 inhibitor (rabbit), and lactoferrin (cow) have both high mannose and complex structures. Collectively, these data represent a beginning point for the future investigation of species-specific and tissue/cell-specific differences in N-glycan structures among animals used for transgenic animal bioreactors

    Analysis of the N-glycans of recombinant human Factor IX purified from transgenic pig milk

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    Glycosylation of recombinant proteins is of particular importance because it can play significant roles in the clinical properties of the glycoprotein. In this work, the N-glycan structures of recombinant human Factor IX (tg- FIX) produced in the transgenic pig mammary gland were determined. Themajority of theN-glycans of transgenic pigderived Factor IX (tg-FIX) are complex, bi-antennary with one or two terminal N-acetylneuraminic acid (Neu5Ac) moieties. We also found that the N-glycan structures of tg-FIX produced in the porcine mammary epithelial cells differed with respect to N-glycans from glycoproteins produced in other porcine tissues. tg-FIX contains no detectableNeu5Gc, the sialic acid commonly found in porcine glycoproteins produced in other tissues.Additionally,wewere unable to detect glycans in tg-FIX that have a terminal Galα(1,3)Gal disaccharide sequence, which is strongly antigenic in humans. The N-glycan structures of tg-FIX are also compared to the publishedN-glycan structures of recombinant human glycoproteins produced in other transgenic animal species.While tg-FIX contains only complex structures, antithrombin III (goat), C1 inhibitor (rabbit), and lactoferrin (cow) have both high mannose and complex structures. Collectively, these data represent a beginning point for the future investigation of species-specific and tissue/cell-specific differences in N-glycan structures among animals used for transgenic animal bioreactors
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