Hindawi Publishing Corporation Anemia Volume 2012, Article ID 507894, 8 pages doi:10.1155/2012/507894 Research Article Induction of Fetal Hemoglobin In Vivo Mediated by a Synthetic γ-Globin Zinc Finger Activator Fl´ avia C. Costa, 1 Halyna Fedosyuk, 1 Renee Neades, 1 Johana Bravo de Los Rios, 1 Carlos F. Barbas III, 2 and Kenneth R. Peterson 1, 3 1 Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA 2 Department of Molecular Biology and Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA 3 Department of Anatomy and Cell Biology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA Correspondence should be addressed to Kenneth R. Peterson, kpeterson@kumc.edu Received 16 February 2012; Revised 17 April 2012; Accepted 24 April 2012 Academic Editor: Betty S. Pace Copyright © 2012 Fl´ avia C. Costa et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 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 A γ -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. 1. Introduction Human hemoglobin is a tetrameric molecule composed of two α-like and two β-like chains, located on chro- mosomes 16 and 11, respectively. The β-like chain is comprised of the product of one of five functional genes (embryonic ε-, fetal A γ- and G γ-, and adult δ - and β- globin) which are developmentally expressed in the order that they are arrayed in the locus [1, 2]. As human erythroid development proceeds, the proper β-like globin genes are activated or repressed, giving rise to the different hemoglobin chains expressed throughout development [2]. Hemoglobin switching from fetal γ-globin to adult β- globin gene expression begins shortly before birth and is usually completed within the first 6 months after birth. In some individuals, hemoglobin switching is not completed, resulting in a condition called hereditary persistence of fetal hemoglobin (HPFH), which is characterized by high expression of fetal hemoglobin (HbF, γ-globin) during adult definitive erythropoiesis [1, 2]. Sickle cell disease (SCD) and β-thalassemia patients are phenotypically normal if they carry compensatory mutations that result in HPFH as well [1, 2]. These genetic studies have indicated that increased HbF will help alleviate pathophysiology associated with these hemoglobinopathies, and thus, research has focused on elucidating the pathways involved in the maintenance or activation of γ-globin expression by drug or gene therapy. Pharmacological agents such as butyrate, decitabine, and hydroxyurea are effective in inducing HbF in vitro and in vivo [3]. To date, hydroxyurea, a ribonucleotide reductase inhibitor, is the only drug approved for clinical use in sickle