Human Molecular Genetics Advance Access originally published online on August 22, 2007
Human Molecular Genetics 2007 16(21):2616-2625; doi:10.1093/hmg/ddm218
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Restoration of the balanced 
/ß-globin gene expression in ß654-thalassemia mice using combined RNAi and antisense RNA approach
Shanghai Institute of Medical Genetics, Shanghai Children’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
* To whom correspondence should be addressed at: 24/1400 West Beijing Road, Shanghai Institute of Medical Genetics, Shanghai Children’s Hospital, Shanghai 200040, People's Republic of China. Tel: +8621 62790545; Fax: +8621 62475476; Email: ytzeng{at}stn.sh.cn
Received June 5, 2007; Accepted August 4, 2007
The ß-thalassemia is associated with abnormality in ß-globin gene, leading to imbalanced synthesis of 
-/ß-globin chains. Consequently, the excessive free -globin chains precipitate to the erythrocyte membrane, resulting in hemolytic anemia. We have explored post-transcriptional strategies aiming at -globin reduction and ß-globin enrichment on ß654 (Hbbth-4/Hbb+) mouse, carrying a human splicing-deficient ß-globin allele (Hbbth-4). Lentiviral vectors of short hairpin RNA (shRNA) targeting -globin and/or antisense RNA facilitating ß-globin correct splicing were microinjected into ß654 single-cell embryos. Three transgenic strains were generated, as i-Hbbth-4/Hbb+(shRNA), ßa-Hbbth-4/Hbb+(antisense) and ißa-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 ißa-Hbbth-4/Hbb+, which correlated with a better-balanced -/ß-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 ß-thalassemia therapy by balancing the synthesis of -/ß-globin chains.
Present address: Binzhou Medical College, Binzhou, ShanDong Province, People's Republic of China.
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