Figure 1.

Pathophysiology of hemoglobin disorders: Prospects for gene therapy. Normal human red cells contain 30 pg of hemoglobin, which in the adult is composed of two α and two β-globin chains (HbA = α₂β₂). The two globin chains are synthesized in nearly equal amounts in maturing erythroblasts. Before birth, γ-globin rather than β-globin is present in the hemoglobin tetramer. During the perinatal period, there is a switch from γ- to β-globin synthesis, resulting in the replacement of HbF with HbA in neonatal red blood cells. (A) Peripheral blood smear from a patient with severe homozygous β-thalassemia. The red blood cells are poorly hemoglobinized. The smear has been stained to depict the insoluble inclusions of α chains. (B) Biosynthesis of globin chains by erythroid cells from a patient with severe homozygous β-thalassemia. Incorporation of the radioactive amino acid into globin chains is characteristically abnormal with excess synthesis of α-globin and deficient synthesis of non-α- (γ- and β-) globin. Effective gene therapy could be achieved by increasing the synthesis of β-globin, the normal adult chain, or γ-globin, which is typically expressed during fetal life. (C) Blood cells from a patient with sickle cell anemia. The characteristic sickle shape reflects polymerization of hemoglobin, which occurs as a consequence of a single amino acid substitution, valine for glutamic acid, at position six on the surface of the hemoglobin molecule. (D) Expression of the naturally, anti-sickling fetal (γ-) globin in red cells from patients with sickle cell anemia reduces sickling propensity as a consequence of the formation of mixed tetramers (α₂β^sγ) in red blood cells. The mixed tetramers are unable to participate in polymerization, thereby effectively reducing the concentration of sickle hemoglobin (Hbα₂β^s₂). Effective gene therapy could be achieved by introducing a functional γ-globin gene that expressed at least 20% the level of β^s globin genes.