Recent advances in β-thalassemias

Abstract

β-thalassemias, a group of autosomal recessive disorders resulting from reduced or absent production of β-globin chains from the β-globin locus, are very heterogeneous at the molecular level (for review see Weatherall & Clegg, 2001 and Cao & Galanello).1-2 More than 200 disease-causing mutations have been described to date. The large majority of mutations are simple nucleotide substitutions or deletions or insertions of oligonucleotides leading to frameshift. Rarely the β-thalassemias are the result of gross gene deletions. Homozygosity for β-thalassemia usually leads to the severe transfusion-dependent phenotype of thalassemia major. Treatment with a regular transfusion program and chelation therapy, aimed at reducing the transfusion iron-overload allows for normal growth and development and extends the life expectancy into the third to fifth decade. Bone marrow or cord blood transplantation (BMT) from an HLA-identical sib represent an alternative to traditional transfusion and chelation therapy. More rarely the homozygous state for β-thalassemia leads to the phenotype of thalassemia intermedia. Individuals with thalassemia intermedia present later, and have milder anemia and only rarely require transfusion. However also patients with thalassemia intermedia are at risk to develop iron overload secondary to increased intestinal iron absorption because of ineffective erythropoiesis. In the last few years there has been a dramatic advancement in the field of chelation therapy, genetic factors ameliorating the clinical phenotype, hemoglobin switching, gene therapy with lentiviral vectors and development of embryonic-like stem cells obtained by transfection and reprogramming differentiated somatic cells with key regulatory factors. All these developments, which are the topics of this review, may lead in the long term to advances in the traditional and in the gene and stem-cell-based therapy.

Keywords

• β-thalassemia
• gene therapy
• iron chelation
• GWAS