Use of Gene Therapy to Induce Transplantation Tolerance

Children'S Hospital Los Angeles, Los Angeles CA

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Abstract

The critical shortage of human organs available for transplantation to patients with end-stage diseases has led to an increasing amount of attention directed at developing methods to allow for the use of pigs as an alternative source of donor organs. Humans that have never been exposed to pig cells, however, have antibodies that are capable of rapidly rejecting these organs. These antibodies react predominantly with a specific sugar called the galactose tx1,3 galactose carbohydrate epitope (gal epitope) expressed on pig cells. This sugar is identified as foreign by humans or Old World primates because a mutation has occurred during evolution that prevents this carbohydrate from being expressed in humans and specific types of monkeys. Consequently, humans produce antibodies to gal when exposed to organs derived from other species (xenografts). A special strain of mice has recently been developed that serves as a good small animal model of xenograft rejection because they produce anti-gal antibodies similar to the antibodies that reject pig xenografts in humans. In this model, production of antibodies that reject pig cells can be prevented by introducing a single gene by bone marrow transplantation before the mouse is exposed to the pig cells. The ability to reproduce this experiment in a preclinical primate model will provide a means by which human patients may be treated prior to xenotransplantation to prevent rejection of pig organs, and will have a significant impact on the field of transplantation. This experiment has not yet been reproduced in primates because introduction of the new gene in primate stem cells of the bone marrow is more difficult compared with the mouse model using conventional methods. We have recently established a new method to introduce genes more efficiently into primate and human stem cells of the bone marrow using a new type of gene delivery vehicle (lentiviral vector). In this application, we propose to introduce the gene responsible for gal carbohydrate expression in primate stem cells and determine whether this procedure prevents anti-gal antibody production in primates. Our hypothesis is that this new vector will allow us to introduce the gene responsible for encoding the gal carbohydrate into primate stem cells at levels that are sufficient to prevent the immune response to pig cells in transplanted rhesus monkeys.