UNC0638 induces high levels of fetal hemoglobin expression in β-thalassemia/HbE erythroid progenitor cells

Nualkaew, Tiwaporn; Khamphikham, Pinyaphat; Pongpaksupasin, Phitchapa; Kaewsakulthong, Woratree; Songdej, Duantida; Paiboonsukwong, Kittiphong; Sripichai, Orapan; Engel, James Douglas; Hongeng, Suradej; Fucharoen, Suthat; Jearawiriyapaisarn, Natee

doi:10.1007/s00277-020-04136-w

Cited by 12 publications

(6 citation statements)

References 40 publications

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“…UNC0638 was able to increase in γ-globin mRNA levels, HbF levels and F cells. This HbF induction was 25.5 ± 4.2% above baseline levels, with a more pronounced effect when added at an early stage (day 4) of erythropoiesis [80]. It is noteworthy that UNC0638 exhibited an HbF-inducing activity similar to pomalidomide, but higher than decitabine under the same culture conditions [80].…”

Section: Ehmt1/2 Inhibitorsmentioning

confidence: 87%

“…This HbF induction was 25.5 ± 4.2% above baseline levels, with a more pronounced effect when added at an early stage (day 4) of erythropoiesis [80]. It is noteworthy that UNC0638 exhibited an HbF-inducing activity similar to pomalidomide, but higher than decitabine under the same culture conditions [80]. UNC0638 shows a synergic effect on HbF synthesis when used in combination with either pomalidomide or decitabine.…”

Section: Ehmt1/2 Inhibitorsmentioning

confidence: 90%

“…This was associated with a decreased accumulation of H3K9me2 near the γ-globin loci and with increased loop formation between the locus control region and the γ-globin promoters through the recruitment of the LDB1 complex to the γ globin promoters [77][78][79]. In a recent study conducted on erythroid precursors derived from CD34+ cells of β 0 -thalassemia/HbE patients, the HbF-inducing activity of UNC0638, either alone or in combination with pomalidomide and decitabine, was investigated [80]. UNC0638 was able to increase in γ-globin mRNA levels, HbF levels and F cells.…”

Section: Ehmt1/2 Inhibitorsmentioning

confidence: 99%

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Pharmacological Induction of Fetal Hemoglobin in β-Thalassemia and Sickle Cell Disease: An Updated Perspective

et al. 2022

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A significant amount of attention has recently been devoted to the mechanisms involved in hemoglobin (Hb) switching, as it has previously been established that the induction of fetal hemoglobin (HbF) production in significant amounts can reduce the severity of the clinical course in diseases such as β-thalassemia and sickle cell disease (SCD). While the induction of HbF using lentiviral and genome-editing strategies has been made possible, they present limitations. Meanwhile, progress in the use of pharmacologic agents for HbF induction and the identification of novel HbF-inducing strategies has been made possible as a result of a better understanding of γ-globin regulation. In this review, we will provide an update on all current pharmacological inducer agents of HbF in β-thalassemia and SCD in addition to the ongoing research into other novel, and potentially therapeutic, HbF-inducing agents.

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Section: Ehmt1/2 Inhibitorsmentioning

confidence: 87%

Section: Ehmt1/2 Inhibitorsmentioning

confidence: 90%

Section: Ehmt1/2 Inhibitorsmentioning

confidence: 99%

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Pharmacological Induction of Fetal Hemoglobin in β-Thalassemia and Sickle Cell Disease: An Updated Perspective

et al. 2022

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“…However, the reactivation of HbF observed upon EHMT1/2 downregulation was associated with an additional activating event, the acetylation of H3 lysine 9 (H3K9Ac) at the HBG1/2 promoters, which is typically associated with gene activation (see paragraph “Histone acetylations”) [ 70 ]. Promisingly, UNC0638 also led to high levels of HbF expression in erythroid cells from β-thalassemia patients [ 72 ]. FTX-6058, and inhibitor of EDD, was also tested in healthy volunteers and induced high HbF levels without major side effects (NCT04586985).…”

Section: Epigenetic Regulation Of the β-Globin Genesmentioning

confidence: 99%

Epigenetic Regulation of β-Globin Genes and the Potential to Treat Hemoglobinopathies through Epigenome Editing

Fontana

Alahouzou

Miccio

et al. 2023

Genes

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Beta-like globin gene expression is developmentally regulated during life by transcription factors, chromatin looping and epigenome modifications of the β-globin locus. Epigenome modifications, such as histone methylation/demethylation and acetylation/deacetylation and DNA methylation, are associated with up- or down-regulation of gene expression. The understanding of these mechanisms and their outcome in gene expression has paved the way to the development of new therapeutic strategies for treating various diseases, such as β-hemoglobinopathies. Histone deacetylase and DNA methyl-transferase inhibitors are currently being tested in clinical trials for hemoglobinopathies patients. However, these approaches are often uncertain, non-specific and their global effect poses serious safety concerns. Epigenome editing is a recently developed and promising tool that consists of a DNA recognition domain (zinc finger, transcription activator-like effector or dead clustered regularly interspaced short palindromic repeats Cas9) fused to the catalytic domain of a chromatin-modifying enzyme. It offers a more specific targeting of disease-related genes (e.g., the ability to reactivate the fetal γ-globin genes and improve the hemoglobinopathy phenotype) and it facilitates the development of scarless gene therapy approaches. Here, we summarize the mechanisms of epigenome regulation of the β-globin locus, and we discuss the application of epigenome editing for the treatment of hemoglobinopathies.

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“…HuDEP2 expansion and differentiation were described previously 10,11 . Human CD34+ HSPC erythroid differentiation were described previously 10,12 . HbF staining was modified from previous publication 13 .…”

Section: Hudep2 Cell Culture and Erythroid Differentiationmentioning

confidence: 99%

Identification of novel γ-globin inducers among all potential erythroid druggable targets

Myers

Schneider

et al. 2022

Blood Advances

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Human γ-globin is predominantly expressed in fetal liver erythroid cells during gestation from two nearly identical genes, HBG1 and HBG2, that are both perinatally silenced. Reactivation of these fetal genes in adult red blood cells can ameliorate many symptoms associated with the inherited β-globinopathies, sickle cell disease (SCD) and Cooley's anemia. While promising genetic strategies to reactivate the γ-globin genes to treat these diseases have been explored, there are significant barriers to their effective implementation worldwide; alternatively, pharmacological induction of γ-globin synthesis could readily reach the majority of affected individuals. In this study, we generated a CRISPR knockout library that targeted all erythroid genes for which prospective or actual therapeutic compounds already exist. By probing this library for genes that repress fetal hemoglobin (HbF), we identified several novel, potentially druggable, γ-globin repressors, including VHL and PTEN. We demonstrate that deletion of VHL induces HbF through activation of the HIF1α pathway and that deletion of PTEN induces HbF through AKT pathway stimulation. Finally, we show that small molecule inhibitors of PTEN and EZH induce HbF in both healthy and β-thalassemic human primary erythroid cells.

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UNC0638 induces high levels of fetal hemoglobin expression in β-thalassemia/HbE erythroid progenitor cells

Cited by 12 publications

References 40 publications

Pharmacological Induction of Fetal Hemoglobin in β-Thalassemia and Sickle Cell Disease: An Updated Perspective

Pharmacological Induction of Fetal Hemoglobin in β-Thalassemia and Sickle Cell Disease: An Updated Perspective

Epigenetic Regulation of β-Globin Genes and the Potential to Treat Hemoglobinopathies through Epigenome Editing

Identification of novel γ-globin inducers among all potential erythroid druggable targets

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