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PRIMARY CELL-MEDIATED GENE TRANSFER- Gene transfer by embryo cloning - Jim Robl Hematech, Inc. AC21 Advisory Committee Meeting November 28, 2007 DNA TRANSFER BY PRIMARY CELL CLONING Vector Primary fibroblast cells Transgenic cells Transfection Selection Embryonic cloning Enucleated oocyte Primary cell – Cell with a finite lifespan Primary Transfection and selection Cell line establishment Transfection and selection Cell line establishment Transfection and selection MULTIPLE GENETIC MODIFICATIONS Additional modifications Clone to Rejuvenate Clone to make Calves Clone to Rejuvenate Clone to Rejuvenate Clone to make Calves 1st Modification 2nd Modification GENE TARGETING STOP SEQUENCE (GENE KNOCKOUT) SELECTION SEQUENCE DNA Sequence (chromosome) Gene Sequence 1st Chromosome 2nd Chromosome Homologous arms Recombination PRION GENE KNOCKOUT CATTLE GENE KNOCKOUT CATTLE IMMUNOGLOBULIN GENE KNOCKOUT CATTLE MICROCHROMOSOME TRANSFER Chromosome Chromosome fragment GENE SEQUENCE OF INTEREST REMOVE UNWANTED GENES Transgenic cells TRANSCHROMOSOMIC CALVES THERAPEUTIC PROTEINS PRODUCED IN MILK Product Company Species Developmental Stage Anti-thrombin III GTC Biotherapeutics Goat EMEA approved US: Phase III C1 Esterase Inhibitor Pharming Rabbit Phase III a-Fetoprotein Merrimack GTC Biotherapeutics Goat Phase II a-Glucosidase Pharming Rabbit Phase II (on hold) Human growth hormone BioSidus Cattle Preclinical Human serum albumin GTC Biotherapeutics Cattle Preclinical Fibrinogen Pharming Cattle Preclinical Collagen Pharming Cattle Preclinical Lactoferrin Pharming Cattle Preclinical a-1 antitrypsin GTC Biotherapeutics Goat Preclinical Malaria vaccine GTC Biotherapeutics Goat Preclinical CD 137 Mab GTC Biotherapeutics Goat Preclinical Niemann, H. W.A. Kues. Reprod Fertil Dev 2007; 19: 762-770. PIG-TO-HUMAN ORGAN TRANSPLANTATION Transgenic trait Key molecule Reference Minimize complement activation Human complement regulatory proteins Cozzi White, 1995 Platt Lin, 1998 Pete