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Human Molecular Genetics Advance Access published online on August 22, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm218
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Restoration of the Balanced {alpha}/ß-globin Gene Expression in ß654–Thalassemia Mice using combined RNAi and Antisense RNA Approach

Shu-Yang Xie{ddagger}, Zhao-Rui Ren, Jing-Zhi Zhang, Xin-Bin Guo, Qing-Xue Wang, Shu Wang, Dan Lin, Xiu-Li Gong, Wei Li, Shu-Zhen Huang, Yi-Tao Zeng* and Fanyi Zeng

Shanghai Institute of Medical Genetics, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China

* To whom correspondence should be addressed at: 24/1400 West Beijing Road, Shanghai Institute of Medical Genetics, Shanghai Children's Hospital, Shanghai 200040, China. Telephone: (8621)62790545, Fax: (8621)62475476, E-Mail: ytzeng{at}stn.sh.cn

Received June 5, 2007; Revised August 4, 2007; Accepted August 4, 2007

ß-thalassemia is associated with abnormality in ß-globin gene, leading to imbalanced synthesis of {alpha}-/ß-globin chains. Consequently, the excessive free {alpha}-globin chains precipitate to the erythrocyte membrane, resulting in hemolytic anemia. We have explored post-transcriptional strategies aiming at {alpha}-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 {alpha}-globin and/or antisense RNA facilitating ß-globin correct splicing were microinjected into ß654 single-cell embryos. Three transgenic strains were generated, as {alpha}i-Hbbth-4/Hbb+(shRNA), ßa-Hbbth-4/Hbb+(antisense) and {alpha}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 {alpha}ißa-Hbbth-4/Hbb+, which correlated with a better-balanced {alpha}-/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%, comparing to 45.4% of untreated. Our data have demonstrated the feasibility of techniques for ß-thalassemia therapy by balancing the synthesis of {alpha}-/ß-globin chains.

{ddagger} Present address: Binzhou Medical College, Binzhou, ShanDong Province, China


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