Cure for thalassemia major - from allogeneic hematopoietic stem cell transplantation to gene therapy

Abstract

Allogeneic hematopoietic stem cell transplantation has been well established for several decades as gene replacement therapy for patients with thalassemia major, and now offers very high rates of cure for patients who have access to this therapy. Outcomes have improved tremendously over the last decade, even in high-risk patients. The limited data available suggests that the long-term outcome is also excellent, with a >90% survival rate, but for the best results, hematopoietic stem cell transplantation should be offered early, before any end organ damage occurs. However, access to this therapy is limited in more than half the patients by the lack of suitable donors. Inadequate hematopoietic stem cell transplantation services and the high cost of therapy are other reasons for this limited access, particularly in those parts of the world which have a high prevalence of this condition. As a result, fewer than 10% of eligible patients are actually able to avail of this therapy. Other options for curative therapies are therefore needed. Recently, gene correction of autologous hematopoietic stem cells has been successfully established using lentiviral vectors, and several clinical trials have been initiated. A gene editing approach to correct the β-globin mutation or disrupt the BCL11A gene to increase fetal hemoglobin production has also been reported, and is expected to be introduced in clinical trials soon. Curative possibilities for the major hemoglobin disorders are expanding. Providing access to these therapies around the world will remain a challenge.

Figure 1.

Evolution of chimerism after hematopoietic stem cell transplantation (HSCT). Early mixed chimerism is associated with higher risk of rejection while late chimerism often persists with a stable graft. RHCs: residual host cells. MC: mixed chimerism.

Figure 2.

Methods to detect red cell chimerism. In patients with late persistent mixed chimerism, erythroid precursors may be predominantly donor while the non-erythroid cells may be more recipient in origin. Red cell chimerism can be measured by analyzing donor specific RBC antigens, STRs in erythroid DNA or nucleotide variations in erythroid transcripts. BFU-E: burst forming unit – erythroid; CFU-E: colony forming unit – erythroid; STR: short tandem repeats; RBC: red blood cell.

Figure 3.

Overview of current approaches to gene therapy for the major hemoglobin disorders. Gene modifications may be through viral vectors or genome editing technologies to achieve the desired therapeutic effect. HSC: Hematopoietic stem cell; BM: Bone marrow; PB: Peripheral blood; ZFN: zinc finger nucleases; TALEN: transcription activator-like effectors with Fokl nuclease; CRISPR: clustered regularly interspaced short palindromic repeats.

Figure 4.

Genome editing techniques for correction of molecular defects. The three different gene editing techniques allow fixing of single mutations in the hemoglobin gene in patients with β-thalassemia major. ZFNs: zinc finger nucleases; TALENs: transcription activator-like effectors with Fokl nuclease; CRISPR: clustered regularly interspaced short palindromic repeats.