title: In vivo activation of the human δ-globin gene: the therapeutic potential in β-thalassemic mice.
abstract: β-thalassemia and sickle cell disease are widespread fatal genetic diseases. None of the existing clinical treatments provides a solution for all patients. Two main strategies for treatment are currently being investigated: (i) gene transfer of a normal β-globin gene; (ii) reactivation of the endogenous γ-globin gene. To date, neither approach has led to a satisfactory, commonly accepted standard of care. The δ-globin gene produces the δ-globin of hemoglobin A2. Although expressed at a low level, hemoglobin A2 is fully functional and could be a valid substitute of hemoglobin A in β-thalassemia, as well as an anti-sickling agent in sickle cell disease. Previous in vitro results suggested the feasibility of transcriptional activation of the human δ-globin gene promoter by inserting a Kruppel-like factor 1 binding site. We evaluated the activation of the Kruppel-like factor 1 containing δ-globin gene in vivo in transgenic mice. To evaluate the therapeutic potential we crossed the transgenic mice carrying a single copy activated δ-globin gene with a mouse model of β-thalassemia intermedia. We show that the human δ-globin gene can be activated in vivo in a stage- and tissue-specific fashion simply by the insertion of a Kruppel-like factor 1 binding site into the promoter. In addition the activated δ-globin gene gives rise to a robust increase of the hemoglobin level in β-thalassemic mice, effectively improving the thalassemia phenotype. These results demonstrate, for the first time, the therapeutic potential of the δ-globin gene for treating severe hemoglobin disorders which could lead to novel approaches, not involving gene addition or reactivation, to the cure of β-hemoglobinopathies.
authors.affiliation: ristaldi@irgb.cnr.it or susanna.porcu@irgb.cnr.it.
authors.forename: Maria F
authors.initials: MF
authors.lastname: Manchinu
authors.forename: Maria F
authors.initials: MF
authors.lastname: Marongiu
authors.forename: Daniela
authors.initials: D
authors.lastname: Poddie
authors.forename: Carla
authors.initials: C
authors.lastname: Casu
authors.forename: Veronica
authors.initials: V
authors.lastname: Latini
authors.forename: Michela
authors.initials: M
authors.lastname: Simbula
authors.forename: Renzo
authors.initials: R
authors.lastname: Galanello
authors.forename: Paolo
authors.initials: P
authors.lastname: Moi
authors.forename: Antonio
authors.initials: A
authors.lastname: Cao
authors.forename: Susanna
authors.initials: S
authors.lastname: Porcu
authors.forename: Maria S
authors.initials: MS
authors.lastname: Ristaldi
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000166:cytology / Q000378:metabolism; D004920:Erythropoiesis / Q000235:genetics; D015870:Gene Expression; D023061:Gene Order; D017930:Genes, Reporter; D056426:Genetic Loci; D006801:Humans; D007501:Iron / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D011401:Promoter Regions, Genetic; D015533:Transcriptional Activation; D017086:beta-Thalassemia / Q000235:genetics* / Q000628:therapy; D055546:delta-Globins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D055546:delta-Globins; D007501:Iron