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The use of gene therapy for immunodeficiency disease
Immunol All Clin N Am
As presently practiced, gene therapy can be defined broadly as "the transfer of exogenous genes to somatic cells of a patient in order to correct an inherited or acquired gene defect, or to introduce a new function or property." The view of gene therapy has evolved from the original concept of it as a novel form of treatment for inherited genetic disorders to the realization that the power of this technique can be used for the treatment of a broad range of non-inherited disorders such as cancer and AIDS. The potential applications of gene therapy have expanded as progress in biotechnology and recombinant DNA techniques have improved our ability to introduce exogenous genetic material into mammalian cells. In addition, advances in molecular genetics have identified an exponentially growing number of the genes responsible for inherited or acquired human disorders and have uncovered other genetic mechanisms that might be exploited therapeutically. Although genetic intervention on germ cells is a controversial and unsettled issue for the scientific and bioethics communities, genetic engineering of somatic cells and tissues (somatic gene therapy) does not pose any fundamental new ethical issues beyond those already facing modern medicine, and the early clinical applications of this technology have demonstrated its general safety. As of March 1996, 106 clinical gene therapy protocols have received final approval from the National Institutes of Health–Recombinant DNA Advisory Committee (RAC), and 58 of them have been initiated with the enrollment of at least one patient. Because several immunodeficiency diseases can be treated successfullyby allogeneic bone marrow transplantation, this heterogeneous group of disorders appears particularly attractive as an early candidate for gene therapy. Because the techniques of gene delivery currently available are relatively crude and inefficient, ex vivo treatment of the patient's cells offers the best chance for successful genetic treatment. Among the few tissues and cell types easily manipulable ex vivo, bone marrow and peripheral blood cells are perhaps the most readily accessible and available. Diseases curable by allogeneic bone marrow transplantation (BMT), where the cells certainly are manipulated ex vivo, theoretically should be treatable by gene therapy procedures that combine ex vivo genetic correction and autologous BMT. In addition, gene therapy should avoid the potential risks of graft-versus-host disease associated with allogeneic BMT. Many disorders of immunity for which the genetic errors have been identified are, therefore, potential candidates for gene-based therapies, provided that the complete sequence of the mutated gene is known and its physiologic function(s) well understood. To design efficient gene therapy strategies for immunodeficiencies, the system used for gene transfer should be able to deliver the therapeutic gene to lymphohemo-poietic cells or progenitors with reasonable efficiency. A limited number of suitable gene delivery methods have been developed and applied to preclinical studies as well as to clinical gene therapy protocols that have generated important preliminary results. The aim of this article is to the describe molecular aspects of strategies presently available for clinical gene transfer and to discuss current applications and prospects of gene-based therapies for genetic disorders of immunity.
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