Cell-based Genetic Therapy for the Induction of Foetal Haemoglobin in Sickle Cell Disease and Transfusion-dependent β-thalassaemia

Abstract

Sickle cell disease and β-thalassaemia can be ameliorated or perhaps even 'cured' if most erythrocytes can be induced to contain high levels of foetal haemoglobin. While this is not yet possible using foetal haemoglobin-inducing drugs, it might be feasible with cell-based gene therapy. After mobilization of autologous haematopoietic stem and progenitor cells, these cells are engineered with vectors that lead to the derepression of foetal haemoglobin genes or add a globin gene that mimics the effects of foetal haemoglobin. Auto-transplantation after myeloablative conditioning is associated with levels of foetal haemoglobin or an antisickling haemoglobin of about 40% of total haemoglobin. In nearly every patient symptoms of sickle cell disease disappear; patients with β-thalassaemia rarely require blood transfusions. In both groups of patients anaemia is absent or minimal. Optimistically, treated patients appear functionally 'cured'. These are very early days of gene therapy. Less than 200 patients have been followed, usually for no more than 5 years. It is highly likely that improved methods that are being intensively studied will simplify gene therapy leading to its wider applicability for individuals with these very common monogenic diseases.