Nearly 30 years ago, the initial report of a child with thalassemia major who was treated successfully with allogeneic bone marrow transplantation (BMT) established the potential to cure this disorder using cellular therapy. The decades that followed witnessed the evolution from a therapy that was restricted initially to those who had a human leukocyte antigen–identical sibling donor and satisfied restrictive eligibility criteria to the current era, in which improved outcomes after unrelated and sibling donor transplantation among high-risk and good-risk recipients have converged. Despite this considerable progress, however, very few individuals with thalassemia major are treated with BMT, and therefore only a small fraction of all patients with thalassemia worldwide have been cured.
The reasons that so few individuals with thalassemia pursue transplantation are numerous and complex. BMT is an intensive and expensive procedure, and it is not available in all regions of the world where thalassemia is endemic. In addition, in the 30 years during which transplantation efficacy and safety were refined, parallel advances also occurred in supportive health care. As a consequence, outcomes in patients with thalassemia who reside in developed countries have improved dramatically, with projections of survival into the sixth and seventh decades of life. Hence, many affected families and their health-care providers are reluctant to pursue curative therapy that carries a risk of mortality. Moreover, the benefit of cure—in terms of freedom from red blood cell (RBC) transfusions and eliminating iron overload and its health risks—is mitigated by a perception that chronic graft-versus-host disease can cause similar impairments in the quality of life, thus representing the replacement of one chronic health condition for another.
It is against this backdrop of therapeutic decision making that replacement gene therapy must earn its bona fides. While initially touted as a safer alternative to allogeneic BMT by eliminating the risk of graft-versus-host disease, it too will undergo careful scrutiny with regard to risk–benefit considerations. Establishing viral transduction into hematopoietic stem cells (HSCs) to generate safe, stable, erythroid-specific replacement gene expression at a level that is sufficient to have a clinical effect has been challenging. The necessity of fulfilling all these criteria makes this genetic disorder among the most complex to treat successfully with gene therapy. A report by Roselli et al. (EMBO Mol Med, in press) shows that these considerations can be addressed systematically and provides reassurances about the ability to assess safety and efficacy of a clinical trial for thalassemia. A recent report of successful lentiviral β-globin gene transfer associated with RBC transfusion independence in a current gene therapy trial in France also builds confidence in the potential for clinical application (Cavazzana-Calvo et al., Nature, in press).
However, there will be obstacles in the form of high-cost and limited access that will make it very challenging to broaden the availability of gene therapy to affected individuals if and when its therapeutic value has been established. In addition, the apparent requirement of marrow ablation (whether partial or full) to ensure a therapeutic representation of transduced progenitor cells and the possibility that ex vivo manipulation of HSCs might impair proliferative potential and thereby delay or abrogate hematopoietic recovery after high-dose chemotherapy will necessitate clinical testing and safety assessment. A focus on vector safety, particularly with regard to genotoxicity, is of paramount importance in any clinical trial of gene therapy, and it is encouraging to note that Roselli et al. observed no “hot spots” for lentiviral integration. However, the recent clinical report of the emergence of a partially dominant clonal cell population after lentiviral insertion of a β-globin gene vector into the HMG2A locus is concerning and will require careful follow-up in the long term. These initial clinical trial experiences will have an important impact on future application of gene therapy for thalassemia. As with BMT, it will not be feasible to conduct randomized studies comparing curative therapies with supportive care, and attitudes will be profoundly affected by these safety considerations. Nonetheless, we appear to be transitioning to a period in which cautious optimism about the possibility of replacement gene therapy for thalassemia is warranted.