Thalassemia Research Center

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Research Goals

Thalassemia is one of the most common genetic disorders in the world. In Thailand the frequencies of thalassemias and some abnormal hemoglobins are high. These abnormal genes in different combinations lead to over 60 thalassemia syndromes. Thalassemia is characterized by reduced or absente production of either one or more normal globin chains. The main pathology of thalassemia is due to the accumulation of unpaired globin chains in erythrocyte precursors and red blood cells. This leads to ineffective erythropoiesis nand shortened red-cell survival, resulting in severe anemia in the patients. By the sheer mumber of patients, thalassemias are causing an increasingly severe health burden and serious drain on health-care resources of the countries and becoming is one of the major public health problem. The research plans for Thalassemia Research Center can be categorized as follows:

Genotype-phenotype interaction in beta-thalassemia

Despite the same genotype a remarkable variability in severity of beta-thalassemia ranging from nearly asymptomatic to transfusion-dependent is observed. As the main pathology of thalassemia is due to the accumulation of unpaired globin chains in erythrocyte precursors cells. The known genetic factors that influence the degree of imbalanced globin chains are as nature of the beta-globin mutation, coinheritance of alpha-thalassemia gene and association with increased Hb F. However, excluding the known major modifier factors, phenotypic variability in beta-thalassemia/Hb E patients remains unpredictable. The genotype-phenotype interaction in beta-thalassemia and DNA polymorphism that may determine the disease severity and drug metabolism in the patients are being studied.

Regulation of erythropoiesis and mechanism of ineffective erythropoiesis

The anemia in the patients results from the accumulation of unpaired globin chains in erythrocyte precursors, which lead to ineffective erythropoiesis. Thalassemic erythroid precursors underwent apoptosis at a rate that was 3 to 4 times normal. Erythropoiesis is a complex multistep process encompassing proliferation and differentiation of hematopoietic stem cells to mature erythrocytes. The process is mediated by combination of regulatory proteins, acting n condert direct to the development of the progeitor cells into mature erythrocytes. Important growth factors also have been shown to deliver survival/proliferation signals to erythroid progenitor cells. Moreover, during erythropoiesis, numerous miRNAs are induced or repressed. Role of miRNA, signaling pathway on the regulation of erythropoiesis and ineffective erythropoiesis will by explored.

Novel treatments

Treatment of the beta-thalassemia patients are blood transfusion and if possible, iron chelator. The only cured for thalassemia is bone marrow trasplantation. Alternative treatment is required. As the major cause of anemia in beta-thalassemia is secondary to imbalanced globin chain synthesis. Reduction of excess alpha-globin chains by Hb F induction with natural products and synthetic compounds, reduced alpha-globin expression by siRNA and correction of abnormal beta-globin pre-mRNA splicing by antisense oligonucleotide will be studied. Moreover, development of vial vector for gene transfer to hematopoietic cells will also be examined.