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- Title
Restoration of the balanced α/β-globin gene expression in β654-thalassemia mice using combined RNAi and antisense RNA approach.
- Authors
Xie, Shu-Yang; Ren, Zhao-Rui; Zhang, Jing-Zhi; Guo, Xin-Bin; Wang, Qing-Xue; Wang, Shu; Lin, Dan; Gong, Xiu-Li; Li, Wei; Huang, Shu-Zhen; Zeng, Fanyi; Zeng, Yi-Tao
- Abstract
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 (Hbbth-4/Hbb+) mouse, carrying a human splicing-deficient β-globin allele (Hbbth-4). Lentiviral vectors of short hairpin RNA (shRNA) targeting α-globin and/or antisense RNA facilitating β-globin correct splicing were microinjected into β654 single-cell embryos. Three transgenic strains were generated, as αi-Hbbth-4/Hbb+(shRNA), βa-Hbbth-4/Hbb+(antisense) and αiβa-Hbbth-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-Hbbth-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 (Hbbth-4/Hbbth-4) had been viable, and the 3-week survival rate for heterozygotes (Hbbth-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.
- Publication
Human Molecular Genetics, 2007, Vol 16, Issue 21, p2616
- ISSN
0964-6906
- Publication type
Article
- DOI
10.1093/hmg/ddm218