siRNA-mediated reduction of alpha-globin results in phenotypic improvements in beta-thalassemic cells.

Abstract

beta-thalassemia is an inherited hemoglobinopathy caused by defective synthesis of the beta-globin chain of hemoglobin, leading to imbalanced globin chain synthesis. Excess alpha-globin precipitates in erythroid progenitor cells resulting in cell death, ineffective erythropoiesis and severe anemia. Decreased alpha-globin synthesis leads to milder symptoms, exemplified in individuals who co-inherit alpha- and beta-thalassemia. In this study, we investigated the feasibility of utilizing short-interfering RNA (siRNA) to mediate reductions in alpha-globin expression. A number of siRNA sequences targeting murine alpha-globin were tested in hemoglobinized murine erythroleukemic cells. One highly effective siRNA sequence (si-alpha 4) was identified and reduced alpha-globin by approximately 65% at both the RNA and the protein level. Electroporation of si-alpha 4 into murine thalassemic primary erythroid cultures restored alpha :beta-globin ratios to balanced wild-type levels and resulted in detectable phenotypic correction. These results indicate that siRNA-mediated reduction of alpha-globin has potential therapeutic applications in the treatment of beta-thalassemia.

• Authors: Hsiao Phin Joanna Voon, Hady Wardan, Jim Vadolas
• Journal: Haematologica (Haematologica) Vol. 93 Issue 8 Pg. 1238-42 (Aug 2008) ISSN: 1592-8721 [Electronic] Italy
• PMID: 18556409 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• RNA, Small Interfering
• Globins

Topics

• Animals
• Cell Death
• Disease Models, Animal
• Gene Expression Regulation
• Globins (deficiency, genetics)
• Humans
• Leukemia, Erythroblastic, Acute (blood)
• Mice
• Mice, Knockout
• Phenotype
• Polymerase Chain Reaction
• RNA, Small Interfering (genetics, therapeutic use)
• beta-Thalassemia (blood, genetics, pathology, therapy)