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The β-thalassemia is associated with abnormality in β-globin gene, leading to imbalanced synthesis of α-/β-globin chains. Consequently, the excessive free α-globin chains precipitate to the erythrocyte membrane, resulting in hemolytic anemia. We have explored post-transcriptional strategies aiming at α-globin reduction and β-globin enrichment on β654(Hbb   th-4   /Hbb   +) mouse, carrying a human splicing-deficient β-globin allele (Hbb   th-4). Lentiviral vectors of short hairpin RNA (shRNA) targeting α-globin and/or antisense RNA facilitating β-globin correct splicing were microinjected into β654single-cell embryos. Three transgenic strains were generated, as αi-Hbb   th-4   /Hbb   +(shRNA), βa-Hbb   th-4   /Hbb   +(antisense) and αiβa-Hbb   th-4   /Hbb   +(both shRNA and antisense). Without notable abnormalities, all the founders and their offsprings showed sustained amelioration of hematologic parameters, ineffective erythropoiesis and extramedullary hematopoiesis. Augmented effects appeared in αiβa-Hbb   th-4   /Hbb   +, which correlated with a better-balanced α-/β-globin mRNA level. Among the transgenic mice integrated with shRNA and antisense RNA, one homozygous mouse (Hbb   th-4   /Hbb   th-4) had been viable, and the 3-week survival rate for heterozygotes (Hbb   th-4   /Hbb   +) was 97%, compared with 45.4% for untreated. Our data have demonstrated the feasibility of techniques for β-thalassemia therapy by balancing the synthesis of α-/β-globin chains.

human molecular genetics

Restoration of the balanced α/β-globin gene expression in β              654              -thalassemia mice using combined RNAi and antisense RNA approach