Skip Navigation


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
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplementary Data
Right arrow All Versions of this Article:
16/21/2616    most recent
ddm218v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Xie, S.-Y.
Right arrow Articles by Zeng, Y.-T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Xie, S.-Y.
Right arrow Articles by Zeng, Y.-T.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

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

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 {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%, compared with 45.4% for untreated. Our data have demonstrated the feasibility of techniques for ß-thalassemia therapy by balancing the synthesis of {alpha}-/ß-globin chains.

{dagger} Present address: Binzhou Medical College, Binzhou, ShanDong Province, People's Republic of China.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer:
Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.