Comment on Thrasher et al, page 4255
Gene therapy can not be reserved as a “salvage therapy” in SCID-X1 patients failing bone marrow transplantation.
Thrasher and colleagues report in this issue of Blood on the failure of gene therapy to correct immune function when attempted in 2 patients aged 15 and 20 years with X-linked severe combined immunodeficiency (SCID-X1). Besides the implications for the timing of gene therapy, the study also further demonstrates the rapid and irreversible aging of the thymus, and highlights the difficulties of completely recreating an immune system beyond early childhood.
Children with severe forms of SCID, in particular SCID-X1, usually die at less than 1 year of age from opportunistic infections. Long-term survival is possible only with allogeneic stem cell transplantation (SCT), but delayed diagnosis can result in severe infections that preclude successful transplantation.1 Even with early allogeneic transplantation, in particular with haploidentical parental donors, there is incomplete engraftment, with progressive defects in T-cell immunity and a complete lack of donor B cells, resulting in dependency on monthly intravenous infusions of immunoglobulin. These poor outcomes stimulated intense interest in gene therapy approaches to SCID.
In about 50% of all cases, SCID is inherited as an X-linked recessive disease characterized by a block in T and natural killer (NK) lymphocyte differentiation. The defective gene encodes the common cytokine receptor γ-chain, located on the X chromosome. The report of complete immune correction of young SCID-X1 boys by transduction of their CD34+ bone marrow cells with a retroviral vector encoding the common γ-chain, and reinfusion of transduced cells without conditioning therapy, was very encouraging and represented the first unequivocal demonstration of gene therapy efficacy.2,3 However, worryingly, 2 children in this trial developed T-cell leukemia due to insertion of the retroviral vector near the promoter of the proto-oncogene LMO2,4 and a third child out of a total of 11 entered in the trial was recently also reported to have T-cell leukemia. Thus, at present the risks and potential benefits of gene therapy for this disease are being reconsidered.
Thrasher and colleagues now report the failure of gene therapy to produce therapeutic effects and T-cell reconstitution despite successful CD34+ cell transduction in 2 patients with SCID-X1 aged 15 and 20 years, both enrolled in the trial at these advanced ages due to gradual failure of immune function following bone marrow transplantation (BMT). Whether the apparent impossibility for productive thymopoiesis in these patients was the result of previous infections, graft-versus-host disease (GVHD), or physiological aging of the thymus remains hypothetical. It mirrors the observed correlation between patient age at the time of BMT and poor immune outcome in SCID-X1 (eg, Patel et al5 ). This is a very important finding regarding the current discussion about the optimal treatment strategy in the absence of human leukocyte antigen (HLA)–matched donors for SCID-X1 patients. It appears that gene therapy can not be reserved as a “salvage therapy” in SCID-X1 patients failing or not maintaining immune function following BMT. There is a need to compare the oncogenic potential of different vectors in relevant animal models in order to develop safer gene therapy approaches based on their potential for insertional activation of oncogenes, but, as the work of Thrasher and colleagues demonstrates, additional efforts are also required to better understand the biology of diseases that are candidates for therapeutic genetic intervention to design optimal treatment strategies. ▪
