Gene therapy fulfilling its promise.

From its earliest conception, gene therapy held the promise of correcting inherited diseases by inserting a normal copy of the relevant gene into somatic cells.1 Common monogenic diseases of blood cells, such as sickle cell disease or β-thalassemia, were originally considered important candidates for gene therapy because they were well understood at the molecular level and because the target cell, the hematopoietic stem cell, is easily accessible and can be explanted, genetically corrected in the laboratory, and then retransplanted.2 The advantage of gene therapy over the conventional transplantation of hematopoietic stem cells from compatible donors is that gene therapy is in principle available to all patients and should avert the problems of the immunologic barriers that can lead to graft rejection or graft-versus-host disease. It was soon recognized, however, that the technical challenges of correcting hemoglobin disorders by means of gene therapy were daunting, most likely requiring gene transfer in high numbers of hematopoietic stem cells and high levels of expression of the β-globin gene in erythrocyte precursors. Thus, in the mid-1980s, several groups turned to a far rarer disorder, severe combined immunodeficiency disease (SCID) due to deficiency of the enzyme adenosine deaminase (ADA), which was considered to be potentially more tractable with the gene-transfer techniques that were then available. It was known from experience with patients who had SCID and an HLA-matched sibling who could be a hematopoietic stem-cell donor that there is a strong selective-amplification effect whereby only a small amount of engrafted marrow can completely restore the immune system.3 Thus, if the ADA gene could be inserted even into only a modest number of hematopoietic stem cells obtained from a patient with SCID due to ADA deficiency and be expressed in the progeny blood cells produced after retransplantation of the transduced cells, there is a good chance of clinical benefit. Initial efforts at gene therapy for SCID due to ADA deficiency in the early 1990s did not produce the cures that had been hoped for, probably because of the low numbers of gene-corrected hematopoietic stem cells that were engrafted in the first handful of patients.4,5 These pioneer experiments were followed by incremental improvements in the laboratory techniques used to introduce genes into hematopoietic stem cells, and a second generation of clinical trials were begun in the late 1990s, directed at both SCID due to ADA deficiency and the X-linked form of SCID. Thus, in 2000 and 2002, investigators from France and Italy reported results suggesting that the fulfillment of the promise of gene therapy was at hand. Cavazzana-Calvo et al.6 reported immune reconstitution in five infants with X-linked SCID who underwent gene therapy in Paris, and Aiuti et al.7 described initial signs of immune reconstitution in two infants with SCID due to ADA deficiency treated in Milan. The gene-transfer methods used in the two studies were similar, but only the patients with SCID due to ADA deficiency were given a chemotherapeutic agent, busulfan, intended to “make space” for the gene-corrected hematopoietic stem cells to enhance their engraftment after reinfusion. Except for the expected transient neutropenia and thrombocytopenia, the clinical effects of the reduced dose of busulfan chemotherapy used in the study were much milder than those of the “full-dose” conditioning typically used for bone marrow transplantation. Since these two studies were published, the encourag-