Gene therapy for the hemoglobin disorders: past, present, and future.

Abstract

With the development in the early 1980s of technology to transfer genes to murine hematopoietic stem cells by using recombinant murine oncoretroviral vectors (1), the possibility of genetic therapy for a number of human disorders of the lympho-hematopoietic system seemed an attainable goal. Hemoglobin disorders were among the first diseases to be considered for gene therapy. Both sickle cell disease and the thalassemias are common monogenic disorders worldwide that cause serious morbidity and mortality. The pathophysiology of these disorders is amenable to correction by the addition of a functional globin gene to stem cells with subsequent high level expression in maturing erythroid cells (Fig. 1). Encouraging reports of successful transfer of a β-globin gene into the hematopoietic stem cells of mice using an oncoretroviral vector appeared in 1988 (2, 3). Erythroid lineage-specific expression of the globin gene was observed, but the levels of expression were much too low (<1% of mouse β-globin) for a potential therapeutic effect. Recent studies using murine models of both sickle cell disease and β-thalassemia and γ-globin expressing transgenic mice substantiate the clinical impression that sustained expression of a transferred globin gene in the range of 10–20% of the level of endogenous globin in a majority of developing erythroblasts will be required for a therapeutic benefit (4).† 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 …