Therapeutic Approaches for Congenital Immunodeficiencies

The current treatment of immunodeficiencies has two aims: to minimize and control infections and to replace the defective or absent components of the immune system by adoptive transfer or transplantation. Passive immunization with pooled gamma globulin is very beneficial for agammaglobulinemic patients and has been lifesaving for many boys with X-linked agammaglobulin-emia. Hematopoietic stem cell transplantation is currently the treatment of choice for many immunodeficiency diseases and has been successful in the treatment of SCID with ADA deficiency, Wiskott-Aldrich syndrome, bare lymphocyte syndrome, and leukocyte adhesion deficiencies. It is most successful with careful T cell depletion from the marrow and HLA matching to prevent graft-versus-host disease (see Chapter 16). Enzyme replacement therapy for ADA and PNP deficiencies has been attempted, with red blood cell transfusions used as a source of the enzymes. This approach has produced temporary clinical improvement in several patients with autosomal SCID. Injection of bovine ADA conjugated to polyethylene glycol to prolong its serum half-life has proved successful in some cases, but the benefits are usually short-lived.

In theory, the therapy of choice for congenital disorders of lymphocytes is to replace the defective gene in self-renewing stem cells. Gene replacement remains a distant goal for most human immunodeficiencies at present, despite considerable effort. The main obstacles to this type of gene therapy are difficulties in purifying self-renewing stem cells, which are the ideal target for introduction of the replacement gene, and in introducing genes into cells to achieve stable, long-lived, and highlevel expression. Some progress has been made in gene therapy for ADA deficiency by use of a milder conditioning approach to deplete host bone marrow cells, which facilitates the grafting and proliferation of modified stem cells introduced into the host. A small number of patients with X-linked SCID have been successfully treated by transplantation of autologous bone marrow cells engineered to express a normal yc gene. However, a few treated patients have developed leukemia, apparently because the introduced yc gene inserted adjacent to an oncogene and activated this gene. As a result, the future of gene therapy for this disease is uncertain.

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