Key Information
Abstract
β-thalassemia and sickle cell disease are two inherited hematological diseases due to defective hemoglobin synthesis or to the production of hemoglobin with altered properties. These two conditions have prolonged survival with modern support therapies, albeit life-long, complex, expensive and resource-consuming. Studies carried out in the last three decades have shown that allogeneic hematopoietic stem cell transplantation (allo-HSCT) and gene therapy may offer a curative approach for these diseases. Allo-HSCT should be performed early in life to reduce disease-related complications like irreversible tissue damage due to iron overload in patients with transfusion-dependent β-thalassemia (TDT) and systemic vasculopathy in patients with sickle cell disease (SCD). HSCTs from a matched-sibling donor or a matched-unrelated donor represent the best therapeutic option; however, haploidentical HSCT in both TDT and SCD is now increasingly performed as a valuable and viable option for a larger number of these patients. An alternative curative strategy is based on gene therapy. These curative approaches, particularly those of gene therapy, are available only in a part of the world. Gene therapy diffusion is strongly limited by its high technological and infrastructure requirements and its very high cost. Criteria must be defined for the optimal selection of TDT and SCD patients for allo-HSCT or gene therapy.
Keywords: hemoglobinopathies, β-thalassemia, sickle cell disease, hematopoietic stem cell transplantation, gene therapy
1. Introduction
Hemoglobin is the main protein responsible for oxygen transportation in the human body and the major component of red blood cells. The adult HbA (α2β2) is a tetrameric protein whose coding genes are in two separate globin gene cluster families sited on different chromosomes. During fetal life, the fetal hemoglobin (α2γ2) is the predominant hemoglobin, and at birth, HbF is progressively replaced by HbA. When compared to HbA, HbF has a higher affinity for oxygen. The P50 of HbF is lower than the P50 of HbA; this higher affinity of HbF for oxygen is important to obtain oxygen from maternal circulation. This property of HbF is important and was exploited in some studies of gene therapy.
Hemoglobinopathies, the genetic diseases caused by mutations of globin genes, represent the most common monogenic disorders worldwide. The genetic causes of hemoglobinopathies are represented by DNA mutations in or near the globin genes. These DNA variants may cause a defect in globin synthesis (thalassemia) or the synthesis of a mutant, defective hemoglobin, causing diseases such as sickle cell disease (SCD).