Restoration of the balanced α/β-globin gene expression in β 654 -thalassemia mice using combined RNAi and antisense RNA approach

Xie, Shengsong; Ren, Zhaorui; Zhang, Jingzhi; Guo, Xiaofeng; Wang, Qingxue; Wang, Shu; Lin, Dan; Gong, Xiaohua; Li, Wei; Huang, Shu‐Zhen; Zeng, Fanyi; Zeng, Yi‐Tao

doi:10.1093/hmg/ddm218

Cited by 46 publications

(42 citation statements)

References 25 publications

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“…Xie et al performed an in vivo experiment to knock down a-globin expression by shRNA in a b-thalassemia mouse model. 84 Lentiviral vectors of shRNA targeting a-globin were microinjected into b-thalassemia heterozygous mouse single-cell embryos, and a transgenic mouse was generated that produced 20% to 35% less a-globin. These mice demonstrated sustained phenotypic improvement in red cells with less poikilocytosis, fewer target cells, increased hemoglobin values and red cell counts, and low reticulocyte counts.…”

Section: 79mentioning

confidence: 99%

α-Globin as a molecular target in the treatment of β-thalassemia

Mettananda

Gibbons

Higgs

2015

Blood

127

120

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The thalassemias, together with sickle cell anemia and its variants, are the world’s most common form of inherited anemia, and in economically undeveloped countries, they still account for tens of thousands of premature deaths every year. In developed countries, treatment of thalassemia is also still far from ideal, requiring lifelong transfusion or allogeneic bone marrow transplantation. Clinical and molecular genetic studies over the course of the last 50 years have demonstrated how coinheritance of modifier genes, which alter the balance of α-like and β-like globin gene expression, may transform severe, transfusion-dependent thalassemia into relatively mild forms of anemia. Most attention has been paid to pathways that increase γ-globin expression, and hence the production of fetal hemoglobin. Here we review the evidence that reduction of α-globin expression may provide an equally plausible approach to ameliorating clinically severe forms of β-thalassemia, and in particular, the very common subgroup of patients with hemoglobin E β-thalassemia that makes up approximately half of all patients born each year with severe β-thalassemia.

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Section: 79mentioning

confidence: 99%

α-Globin as a molecular target in the treatment of β-thalassemia

Mettananda

Gibbons

Higgs

2015

Blood

127

120

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“…Although a recent study has demonstrated slight phenotypic improvements in transgenic mice expressing short-hairpin RNA targeting α-globin, the authors concede that this is not applicable in a therapeutic setting. 17 In this study, we report that siRNA can be used to reduce expression of a highly expressed gene such as α-globin at both the RNA and protein level. To the best of our knowledge, this is the first study demonstrating definitive reduction of endogenous globins mediated directly with siRNA without any DNA intermediates.…”

Section: Sirna Mediated Reduction Of α α-Globin In Erythroid Progenitmentioning

confidence: 99%

siRNA-mediated reduction of -globin results in phenotypic improvements in -thalassemic cells

2008

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ABSTRACTβ-thalassemia is an inherited hemoglobinopathy caused by defective synthesis of the β-globin chain of hemoglobin, leading to imbalanced globin chain synthesis. Excess α-globin precipitates in erythroid progenitor cells resulting in cell death, ineffective erythropoiesis and severe anemia. Decreased α-globin synthesis leads to milder symptoms, exemplified in individuals who co-inherit α-and β-thalassemia. In this study, we investigated the feasibility of utilizing short-interfering RNA (siRNA) to mediate reductions in α-globin expression. A number of siRNA sequences targeting murine α-globin were tested in hemoglobinized murine erythroleukemic cells. One highly effective siRNA sequence (si-α4) was identified and reduced α-globin by approximately 65% at both the RNA and the protein level. Electroporation of si-α4 into murine thalassemic primary erythroid cultures restored α:β-globin ratios to balanced wild-type levels and resulted in detectable phenotypic correction. These results indicate that siRNA-mediated reduction of α-globin has potential therapeutic applications in the treatment of β-thalassemia.Key words: siRNA-mediated reduction, α-globin, phenotypic, β-thalassemic cells.Citation: Voon HPJ, Wardan H, and Vadolas J. siRNA-mediated reduction of α-globin results in phenotypic improvements in β-thalassemic cells.

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“…Há uma tentativa de compensação pela medula óssea, com aceleração da produção de eritrócitos, porém insuficiente para [125][126][127] .…”

Section: Fisiopatologiaunclassified

The genetics of blood disorders: the hereditary hemoglobinopathies

Sonati¹,

Costa²

2008

J Pediatr (Rio J)

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ResumoObjetivo: Sumarizar os dados disponíveis na literatura recente sobre os aspectos fisiopatológicos, de diagnóstico e tratamento das doenças falciformes e da talassemia β, hemoglobinopatias hereditárias de maior relevância nas populações. Fontes dos dados AbstractObjective: To summarize recently published data on the pathophysiology, diagnosis and treatment of sickle cell diseases and β-Thalassemias, the most relevant hereditary hemoglobinopathies in the global population.Sources: Searches were run on the MEDLINE and SCIELO databases, limited to the period from 2003 to May 2008, using the terms hereditary hemoglobinopathies, sickle cell diseases and β-thalassemia. Two books and two chapters were also included. Summary of the findings:More than 2,000 articles were identified; those providing the most important information and broadest views were selected.Conclusions: Morbidity and mortality rates from sickle cell diseases and β-thalassemia are still very high and represent an important challenge. Increased understanding of pathophysiological aspects has lead to significant improvements in treatment and prevention of these diseases.

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Restoration of the balanced α/β-globin gene expression in β 654 -thalassemia mice using combined RNAi and antisense RNA approach

Cited by 46 publications

References 25 publications

α-Globin as a molecular target in the treatment of β-thalassemia

α-Globin as a molecular target in the treatment of β-thalassemia

siRNA-mediated reduction of -globin results in phenotypic improvements in -thalassemic cells

The genetics of blood disorders: the hereditary hemoglobinopathies

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