Restoration of the balanced α/β-globin gene expression in β654-thalassemia mice using combined RNAi and antisense RNA approach
Identifieur interne : 002B88 ( Main/Exploration ); précédent : 002B87; suivant : 002B89Restoration of the balanced α/β-globin gene expression in β654-thalassemia mice using combined RNAi and antisense RNA approach
Auteurs : Shu-Yang Xie ; Zhao-Rui Ren [République populaire de Chine] ; Jing-Zhi Zhang [République populaire de Chine] ; Xin-Bin Guo [République populaire de Chine] ; Qing-Xue Wang [République populaire de Chine] ; Shu Wang [République populaire de Chine] ; Dan Lin [République populaire de Chine] ; Xiu-Li Gong [République populaire de Chine] ; Wei Li [République populaire de Chine] ; Shu-Zhen Huang [République populaire de Chine] ; Fanyi Zeng [République populaire de Chine] ; Yi-Tao Zeng [République populaire de Chine]Source :
- Human Molecular Genetics [ 0964-6906 ] ; 2007.
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.
Url:
DOI: 10.1093/hmg/ddm218
Affiliations:
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sortKey="Wang, Shu" sort="Wang, Shu" uniqKey="Wang S" first="Shu" last="Wang">Shu Wang</name><affiliation wicri:level="1"><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Shanghai Institute of Medical Genetics, Shanghai Children’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Lin, Dan" sort="Lin, Dan" uniqKey="Lin D" first="Dan" last="Lin">Dan Lin</name><affiliation wicri:level="1"><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Shanghai Institute of Medical Genetics, Shanghai Children’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Gong, Xiu Li" sort="Gong, Xiu Li" uniqKey="Gong X" first="Xiu-Li" last="Gong">Xiu-Li Gong</name><affiliation wicri:level="1"><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Shanghai Institute of Medical Genetics, Shanghai Children’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Li, Wei" sort="Li, Wei" uniqKey="Li W" first="Wei" last="Li">Wei Li</name><affiliation wicri:level="1"><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Shanghai Institute of Medical Genetics, Shanghai Children’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Huang, Shu Zhen" sort="Huang, Shu Zhen" uniqKey="Huang S" first="Shu-Zhen" last="Huang">Shu-Zhen Huang</name><affiliation wicri:level="1"><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Shanghai Institute of Medical Genetics, Shanghai Children’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Zeng, Fanyi" sort="Zeng, Fanyi" uniqKey="Zeng F" first="Fanyi" last="Zeng">Fanyi Zeng</name><affiliation wicri:level="1"><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Shanghai Institute of Medical Genetics, Shanghai Children’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Zeng, Yi Tao" sort="Zeng, Yi Tao" uniqKey="Zeng Y" first="Yi-Tao" last="Zeng">Yi-Tao Zeng</name><affiliation wicri:level="1"><country wicri:rule="url">République populaire de Chine</country></affiliation><affiliation wicri:level="1"><country wicri:rule="url">République populaire de Chine</country><wicri:regionArea>To whom correspondence should be addressed at: 24/1400 West Beijing Road, Shanghai Institute of Medical Genetics, Shanghai Children’s Hospital, Shanghai 200040</wicri:regionArea><wicri:noRegion>Shanghai 200040</wicri:noRegion></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Human Molecular Genetics</title><idno type="ISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><publisher>Oxford University Press</publisher><date type="published">2007</date><date type="e-published">2007</date><biblScope unit="vol">16</biblScope><biblScope unit="issue">21</biblScope><biblScope unit="page" from="2616">2616</biblScope><biblScope unit="page" to="2625">2625</biblScope></imprint><idno type="ISSN">0964-6906</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0964-6906</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="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.</div></front></TEI><affiliations><list><country><li>République populaire de Chine</li></country></list><tree><noCountry><name sortKey="Xie, Shu Yang" sort="Xie, Shu Yang" uniqKey="Xie S" first="Shu-Yang" last="Xie">Shu-Yang Xie</name></noCountry><country name="République populaire de Chine"><noRegion><name sortKey="Ren, Zhao Rui" sort="Ren, Zhao Rui" uniqKey="Ren Z" first="Zhao-Rui" last="Ren">Zhao-Rui Ren</name></noRegion><name sortKey="Gong, Xiu Li" sort="Gong, Xiu Li" uniqKey="Gong X" first="Xiu-Li" last="Gong">Xiu-Li Gong</name><name sortKey="Guo, Xin Bin" sort="Guo, Xin Bin" uniqKey="Guo X" first="Xin-Bin" last="Guo">Xin-Bin Guo</name><name sortKey="Huang, Shu Zhen" sort="Huang, Shu Zhen" uniqKey="Huang S" first="Shu-Zhen" last="Huang">Shu-Zhen Huang</name><name sortKey="Li, Wei" sort="Li, Wei" uniqKey="Li W" first="Wei" last="Li">Wei Li</name><name sortKey="Lin, Dan" sort="Lin, Dan" uniqKey="Lin D" first="Dan" last="Lin">Dan Lin</name><name sortKey="Wang, Qing Xue" sort="Wang, Qing Xue" uniqKey="Wang Q" first="Qing-Xue" last="Wang">Qing-Xue Wang</name><name sortKey="Wang, Shu" sort="Wang, Shu" uniqKey="Wang S" first="Shu" last="Wang">Shu Wang</name><name sortKey="Zeng, Fanyi" sort="Zeng, Fanyi" uniqKey="Zeng F" first="Fanyi" last="Zeng">Fanyi Zeng</name><name sortKey="Zeng, Yi Tao" sort="Zeng, Yi Tao" uniqKey="Zeng Y" first="Yi-Tao" last="Zeng">Yi-Tao Zeng</name><name sortKey="Zeng, Yi Tao" sort="Zeng, Yi Tao" uniqKey="Zeng Y" first="Yi-Tao" last="Zeng">Yi-Tao Zeng</name><name sortKey="Zhang, Jing Zhi" sort="Zhang, Jing Zhi" uniqKey="Zhang J" first="Jing-Zhi" last="Zhang">Jing-Zhi Zhang</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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