Pharmacological Induction of Human Fetal Globin Gene in Hydroxyurea-Resistant Primary Adult Erythroid Cells

Chou, Yi-Chun; Chen, Ruei Lin; Lai, Zheng Sheng; Song, Jen Shin; Chao, Yu Sheng; Shen, Che Kun James

doi:10.1128/mcb.00035-15

Cited by 37 publications

(17 citation statements)

References 67 publications

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“…[Decreasing the concentration of 2,3-diphosphoglycerate inhibits polymerization by two mechanisms-increasing oxygen affinity and increasing solubility of HbS (25).] Highthroughput screens have been developed for the induction of HbF (42)(43)(44)(45)(46). The only high-throughput screen for antipolymerization compounds up until now tests for increasing oxygen affinity on isolated hemoglobin solutions, but it does not address the question of cell permeability (47).…”

Section: Discussionmentioning

confidence: 99%

Kinetic assay shows that increasing red cell volume could be a treatment for sickle cell disease

Henry

Hofrichter

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Although it has been known for more than 60 years that the cause of sickle cell disease is polymerization of a hemoglobin mutant, hydroxyurea is the only drug approved for treatment by the US Food and Drug Administration. This drug, however, is only partially successful, and the discovery of additional drugs that inhibit fiber formation has been hampered by the lack of a sensitive and quantitative cellular assay. Here, we describe such a method in a 96-well plate format that is based on laser-induced polymerization in sickle trait cells and robust, automated image analysis to detect the precise time at which fibers distort ("sickle") the cells. With this kinetic method, we show that small increases in cell volume to reduce the hemoglobin concentration can result in therapeutic increases in the delay time prior to fiber formation. We also show that, of the two drugs (AES103 and GBT440) in clinical trials that inhibit polymerization by increasing oxygen affinity, one of them (GBT440) also inhibits sickling in the absence of oxygen by two additional mechanisms.sickle cell | drugs | hemoglobin S | treatment | screening assay

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Section: Discussionmentioning

confidence: 99%

Kinetic assay shows that increasing red cell volume could be a treatment for sickle cell disease

Henry

Hofrichter

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Several clinical trials of gene therapy for β-TM and severe SCD are ongoing in France and in the United States ( Tables 1 and 2 ). Other recent approaches under study for the gene therapy of the β-hemoglobinopathies include pharmacological 23 or genetic induction of γ-globin production through interference with the BCL11A pathway 24 , 25 or disruption of the BCL11A erythroid enhancer by CRISPR/CAS9 technology as well as zinc finger or transcription activator-like effector nuclease, 26 , 27 or even attempts at repairing the defective β A - globin gene in HSCs by genome editing. 28–30 These approaches are at the stage of collecting evidence of efficacy in relevant cell and animal models and scoring potentially untoward off-target events.…”

Section: Introductionmentioning

confidence: 99%

Gene Therapy of the β-Hemoglobinopathies by Lentiviral Transfer of the β^A(T87Q)-GlobinGene

et al. 2016

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β-globin gene disorders are the most prevalent inherited diseases worldwide and result from abnormal β-globin synthesis or structure. Novel therapeutic approaches are being developed in an effort to move beyond palliative management. Gene therapy, by ex vivo lentiviral transfer of a therapeutic β-globin gene derivative (βAT87Q-globin) to hematopoietic stem cells, driven by cis-regulatory elements that confer high, erythroid-specific expression, has been evaluated in human clinical trials over the past 8 years. βAT87Q-globin is used both as a strong inhibitor of HbS polymerization and as a biomarker. While long-term studies are underway in multiple centers in Europe and in the United States, proof-of-principle of efficacy and safety has already been obtained in multiple patients with β-thalassemia and sickle cell disease.

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“…Principally, we know today, some mechanisms that regulate globin gene activity during development (Stamatoyannopoulos 2005). A number of pharmacological agents are available as fetal hemoglobin inducers including hydroxyurea, 5-azacytidine, araC, butyrate, and other short chain fatty acids (Chou et al 2015, Perrine 2011, Steinberg and Rodgers 2001. Although hydroxyurea is the only FDA approved drug for SCD treatment, but it is highly pleiotropic and does not solely modulate g-globin gene expression (Costa et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Modulation of microRNAs expression in hematopoietic stem cells treated with sodium butyrate in inducing fetal hemoglobin expression

Tayebi

Abrishami

Alizadeh

et al. 2016

Artificial Cells, Nanomedicine, and Biotechnology

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Context Inherited hemoglobin diseases are the most common single-gene disorders. Induction of fetal hemoglobin in beta hemoglobin disorders compensate for abnormal chain and ameliorate the clinical complications. Sodium butyrate is used conventionally for fetal hemoglobin induction; it can be replaced by safer therapeutic tools like microRNAs, small non-coding RNAs that control number of epigenetic mechanisms. Objective In this study, we compared the changes in the microRNAs of differentiated erythroid cells between control and sodium butyrate treated groups. The objective is to find significant association between these changes and gamma chain up regulation. Materials and methods First, CD133 hematopoietic stem cells were isolated from cord blood by magnetic cell sorting (MACS) technique. After proliferation, the cells were differentiated to erythroid lineage in culture medium by EPO, SCF, and IL3. Meanwhile, the test group was treated with sodium butyrate. Then, gamma chain upregulation was verified by qPCR technique. Finally, microRNA profiling was performed through microarray assay and some of them confirmed by qPCR. Result Results demonstrated that gamma chain was 5.9-fold upregulated in the treated group. Significant changes were observed at 76 microRNAs, in which 20 were up-regulated and 56 were down-regulated. Discussion Five of these microRNAs including U101, hsa-miR-4726-5p, hsa-miR7109 5p, hsa-miR3663, and hsa-miR940 had significant changes in expression and volume. Conclusion In conclusion, it can be assumed that sodium butyrate can up-regulate gamma chain gene, and change miRNAs expression. These results can be profitable in future studies to find therapeutic goal suitable for such disorders.

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Pharmacological Induction of Human Fetal Globin Gene in Hydroxyurea-Resistant Primary Adult Erythroid Cells

Cited by 37 publications

References 67 publications

Kinetic assay shows that increasing red cell volume could be a treatment for sickle cell disease

Kinetic assay shows that increasing red cell volume could be a treatment for sickle cell disease

Gene Therapy of the β-Hemoglobinopathies by Lentiviral Transfer of the β^A(T87Q)-GlobinGene

Modulation of microRNAs expression in hematopoietic stem cells treated with sodium butyrate in inducing fetal hemoglobin expression

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Pharmacological Induction of Human Fetal Globin Gene in Hydroxyurea-Resistant Primary Adult Erythroid Cells

Cited by 37 publications

References 67 publications

Kinetic assay shows that increasing red cell volume could be a treatment for sickle cell disease

Kinetic assay shows that increasing red cell volume could be a treatment for sickle cell disease

Gene Therapy of the β-Hemoglobinopathies by Lentiviral Transfer of the βA(T87Q)-GlobinGene

Modulation of microRNAs expression in hematopoietic stem cells treated with sodium butyrate in inducing fetal hemoglobin expression

Contact Info

Product

Resources

About

Gene Therapy of the β-Hemoglobinopathies by Lentiviral Transfer of the β^A(T87Q)-GlobinGene