Induction of Fetal Hemoglobin In Vivo Mediated by a Synthetic γ-Globin Zinc Finger Activator
Sickle cell disease (SCD) and β-thalassemia patients are phenotypically normal if they carry compensatory hereditary persistence of fetal hemoglobin (HPFH) mutations that result in increased levels of fetal hemoglobin (HbF, γ-globin chains) in adulthood. Thus, research has focused on manipulating th...
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| Format: | Article |
| Language: | English |
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Wiley
2012-01-01
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| Series: | Anemia |
| Online Access: | http://dx.doi.org/10.1155/2012/507894 |
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| author | Flávia C. Costa Halyna Fedosyuk Renee Neades Johana Bravo de Los Rios Carlos F. Barbas Kenneth R. Peterson |
| author_facet | Flávia C. Costa Halyna Fedosyuk Renee Neades Johana Bravo de Los Rios Carlos F. Barbas Kenneth R. Peterson |
| author_sort | Flávia C. Costa |
| collection | DOAJ |
| description | Sickle cell disease (SCD) and β-thalassemia patients are phenotypically normal if they carry compensatory hereditary persistence of fetal hemoglobin (HPFH) mutations that result in increased levels of fetal hemoglobin (HbF, γ-globin chains) in adulthood. Thus, research has focused on manipulating the reactivation of γ-globin gene expression during adult definitive erythropoiesis as the most promising therapy to treat these hemoglobinopathies. Artificial transcription factors (ATFs) are synthetic proteins designed to bind at a specific DNA sequence and modulate gene expression. The artificial zinc finger gg1-VP64 was designed to target the −117 region of the Aγ-globin gene proximal promoter and activate expression of this gene. Previous studies demonstrated that HbF levels were increased in murine chemical inducer of dimerization (CID)-dependent bone marrow cells carrying a human β-globin locus yeast artificial chromosome (β-YAC) transgene and in CD34+ erythroid progenitor cells from normal donors and β-thalassemia patients. Herein, we report that gg1-VP64 increased γ-globin gene expression in vivo, in peripheral blood samples from gg1-VP64 β-YAC double-transgenic (bigenic) mice. Our results demonstrate that ATFs function in an animal model to increase gene expression. Thus, this class of reagent may be an effective gene therapy for treatment of some inherited diseases. |
| format | Article |
| id | doaj-art-d9636320f60e4fb4a162a69b6bcfb4d5 |
| institution | Kabale University |
| issn | 2090-1267 2090-1275 |
| language | English |
| publishDate | 2012-01-01 |
| publisher | Wiley |
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| series | Anemia |
| spelling | doaj-art-d9636320f60e4fb4a162a69b6bcfb4d52025-08-20T03:24:17ZengWileyAnemia2090-12672090-12752012-01-01201210.1155/2012/507894507894Induction of Fetal Hemoglobin In Vivo Mediated by a Synthetic γ-Globin Zinc Finger ActivatorFlávia C. Costa0Halyna Fedosyuk1Renee Neades2Johana Bravo de Los Rios3Carlos F. Barbas4Kenneth R. Peterson5Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USADepartment of Biochemistry and Molecular Biology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USADepartment of Biochemistry and Molecular Biology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USADepartment of Biochemistry and Molecular Biology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USADepartment of Molecular Biology and Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USADepartment of Biochemistry and Molecular Biology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USASickle cell disease (SCD) and β-thalassemia patients are phenotypically normal if they carry compensatory hereditary persistence of fetal hemoglobin (HPFH) mutations that result in increased levels of fetal hemoglobin (HbF, γ-globin chains) in adulthood. Thus, research has focused on manipulating the reactivation of γ-globin gene expression during adult definitive erythropoiesis as the most promising therapy to treat these hemoglobinopathies. Artificial transcription factors (ATFs) are synthetic proteins designed to bind at a specific DNA sequence and modulate gene expression. The artificial zinc finger gg1-VP64 was designed to target the −117 region of the Aγ-globin gene proximal promoter and activate expression of this gene. Previous studies demonstrated that HbF levels were increased in murine chemical inducer of dimerization (CID)-dependent bone marrow cells carrying a human β-globin locus yeast artificial chromosome (β-YAC) transgene and in CD34+ erythroid progenitor cells from normal donors and β-thalassemia patients. Herein, we report that gg1-VP64 increased γ-globin gene expression in vivo, in peripheral blood samples from gg1-VP64 β-YAC double-transgenic (bigenic) mice. Our results demonstrate that ATFs function in an animal model to increase gene expression. Thus, this class of reagent may be an effective gene therapy for treatment of some inherited diseases.http://dx.doi.org/10.1155/2012/507894 |
| spellingShingle | Flávia C. Costa Halyna Fedosyuk Renee Neades Johana Bravo de Los Rios Carlos F. Barbas Kenneth R. Peterson Induction of Fetal Hemoglobin In Vivo Mediated by a Synthetic γ-Globin Zinc Finger Activator Anemia |
| title | Induction of Fetal Hemoglobin In Vivo Mediated by a Synthetic γ-Globin Zinc Finger Activator |
| title_full | Induction of Fetal Hemoglobin In Vivo Mediated by a Synthetic γ-Globin Zinc Finger Activator |
| title_fullStr | Induction of Fetal Hemoglobin In Vivo Mediated by a Synthetic γ-Globin Zinc Finger Activator |
| title_full_unstemmed | Induction of Fetal Hemoglobin In Vivo Mediated by a Synthetic γ-Globin Zinc Finger Activator |
| title_short | Induction of Fetal Hemoglobin In Vivo Mediated by a Synthetic γ-Globin Zinc Finger Activator |
| title_sort | induction of fetal hemoglobin in vivo mediated by a synthetic γ globin zinc finger activator |
| url | http://dx.doi.org/10.1155/2012/507894 |
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