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15 pages, 1656 KiB

Open AccessArticle

Drugs Repurposing of Molecules Modulating Human Delta Globin Gene Expression via a Model of Transgenic Foetal Liver Cells: Implications for Beta-Hemoglobinopathy Therapeutics

by Michela Simbula, Maria Francesca Manchinu, Stefania Olla, Michela Congiu, Simona Vaccargiu, Cristian Antonio Caria, Daniela Poddie and Maria Serafina Ristaldi

Biomolecules 2025, 15(4), 565; https://doi.org/10.3390/biom15040565 - 11 Apr 2025

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Abstract

Beta-hemoglobinopathies such as beta-thalassemia and sickle cell disease are severe genetic blood disorders affecting the beta globin chain of haemoglobin A (α2β2). Activation of delta globin, the non-alpha globin of HbA2 (α2δ2), could represent a possible approach to improve the clinical severity of these pathologies. Notably, the therapeutic potential of delta globin has been demonstrated in previous studies using a mouse model of beta-thalassemia and sickle cell disease. The present study evaluated delta globin gene activation by small molecules in erythroid cells isolated from transgenic murine foetal liver. A screening of 119 molecules, selected for their potential in drug repurposing, was performed without prior selection based on specific pathways of interest. Three candidates—Nexturastat, Stattic and Palbociclib—were found to have high efficacy on delta globin expression. Palbociclib also proved effective in increasing gamma globin expression. All of these compounds have pharmacokinetic profiles that are beneficial for clinical application, providing potential inducer agents of HbA2 that could have therapeutic effects in the treatment of beta-hemoglobinopathies. Full article

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9 pages, 873 KiB

Open AccessBrief Report

Heterozygosity of the Complex Corfu δ⁰β⁺ Thalassemic Allele (HBD Deletion and HBB:c.92+5G>A) Revisited

by Christos Kattamis, Myrto Skafida, Polyxeni Delaporta, Christina Vrettou, Joanne Traeger-Synodinos, Christalena Sofocleous and Antonis Kattamis

Biology 2022, 11(3), 432; https://doi.org/10.3390/biology11030432 - 11 Mar 2022

Cited by 1 | Viewed by 2576

Abstract

The Corfu δ⁰β⁺ thalassemic allele is a unique thalassemic allele consisting of the simultaneous presence in cis of a deletion of the δ-globin (Hemoglobin Subunit Delta, HBD) and a single nucleotide variant in the β-globin gene (Hemoglobin Subunit Beta, HBB). The allele has, so far, been described in individuals of Greek origin. The objectives of the study are to ascertain the prevalence of the Corfu δ⁰β⁺ allele in comparison to other β-thalassemia variants encountered in Greece using our in-house data repository of 2558 β-thalassemia heterozygotes, and to evaluate the hematological phenotype of Corfu δ⁰β⁺ heterozygotes in comparison to heterozygotes with the most common β⁺- and deletion α⁰- thalassemia variants in Greece. The results of the study showed a relative incidence of heterozygotes with Corfu δ⁰β⁺ at 1.56% of all β-thalassemic alleles, and a distinct hematological phenotype of the heterozygotes characterized by microcytic, hypochromic anemia with normal levels of HbA₂ (Hemoglobin A2) and elevated HbF (Hemoglobin F) levels. The application of a specific methodology for the identification of the Corfu δ⁰β⁺ allele is important for precise prenatal and antenatal diagnosis programs in Greece. Full article

(This article belongs to the Special Issue Thalassemia Research: Focus on Novel Molecular Insights and Clinical Perspectives)

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10 pages, 1595 KiB

Open AccessArticle

Hemoglobin A₂ and Heterogeneous Diagnostic Relevance Observed in Eight New Variants of the Delta Globin Gene

by Noraesah Mahmud, Massimo Maffei, Massimo Mogni, Gian Luca Forni, Valeria Maria Pinto, Giuseppina Barberio, Silvana Ungari, Antonella Maffè, Cristina Curcio, Francesco Zanolli, Raffaella Paventa, Mariarosa Carta, Alberta Caleffi, Mariella Mercadanti, Sauro Maoggi, Giovanni Ivaldi and Domenico Coviello

Genes 2021, 12(11), 1821; https://doi.org/10.3390/genes12111821 - 19 Nov 2021

Cited by 3 | Viewed by 2819

Abstract

Background: Hemoglobin A (Hb A) (α₂β₂) in the normal adult subject constitutes 96–98% of hemoglobin, and Hb F is normally less than 1%, while for hemoglobin A₂ (Hb A₂) (α₂δ₂), the normal reference values are between 2.0 and 3.3%. It is important to evaluate the presence of possible delta gene mutations in a population at high risk for globin gene defects in order to correctly diagnose the β-thalassemia carrier. Methods: The most used methods for the quantification of Hb A₂ are based on automated high performance liquid chromatography (HPLC) or capillary electrophoresis (CE). In particular Hb analyses were performed by HPLC on three dedicated devices. DNA analyses were performed according to local standard protocols. Results: Here, we described eight new δ-globin gene variants discovered and characterized in some laboratories in Northern Italy in recent years. These new variants were added to the many already known Hb A₂ variants that were found with an estimated frequency of about 1–2% during the screening tests in our laboratories. Conclusions: The knowledge recognition of the delta variant on Hb analysis and accurate molecular characterization is crucial to provide an accurate definitive thalassemia diagnosis, particularly in young subjects who would like to ask for a prenatal diagnosis or preimplantation genetic diagnosis. Full article

(This article belongs to the Special Issue Genetic Tests)

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