Gene therapy of primary immunodeficiencies.

Abstract

Gene therapy is often considered the ultimate treatment with its obvious potential advantage, the correction of genetic diseases at the molecular level, as opposed to merely treating the symptoms caused by genetic aberrations. This vision has spurred great interest in the development and clinical application of gene transfer-based therapeutic approaches. Moreover, recent progress in biotechnology and recombinant DNA techniques has greatly improved our understanding of the molecular basis of inherited diseases, providing the knowledge base necessary to attempt their treatment by gene transfer. In the last decade in particular, genetic defects underlying most of the primary immunodeficiency diseases (PIDD) have been identified (see Table 1), opening the way to the possibility of genetic correction. Theoretically, all PIDD that are curable by allogeneic bone marrow transplantation (BMT) are candidates for ex vivo gene therapy. However, because extensive knowledge of the function(s) and regulation of the involved gene is a clear prerequisite to the rational development of new gene-based therapies, diseases caused by mutations of genes whose function is still unclear (e.g. Xlinked agammaglobulinemia, Wiskott-Aldrich syndrome, and Chediak-Higashi syndrome) must await further studies before clinical gene transfer protocols for affected patients can be proposed. Gene transfer into the totipotent hematopoietic stem cell would seem to be the most logical strategy for treating most PIDD. Targeting the stem cell, however, has proven to be a very difficult task for a series of reasons. These include the lack of precise information about the phenotypic characteristics of the "true" self-renewing lymphohematopoietic stem cell capable of reconstituting the immune system and the very low gene transfer efficiency into such a functional unit that is achievable with current techniques. The results of the extensive clinical experience with BMT as treatment of severe combined immunodeficiencies (SCID) and other PIDD have indicated that the pres-