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Special Issue "Thalassemia Research: Focus on Novel Molecular Insights and Clinical Perspectives"

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A special issue of Biology (ISSN 2079-7737).

Deadline for manuscript submissions: 20 July 2023 | Viewed by 15170

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Special Issue Editors

Dr. Michela Grosso

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Guest Editor

Department of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, Naples Italy
Interests: thalassemia; leukemia; gene expression; transcriptional factors; mitochondria function; oxidative stress

Dr. Alexandros Makis

E-Mail Website
Guest Editor

Child Health Dept., Faculty of Medicine, University of Ioannina, P.O. Box 1187, GR-45110 Ioannina, Greece
Interests: hemoglobinopathies; blood disorders; bone marrow diseases

Special Issue Information

The thalassemia syndromes are among the most common human monogenic disorders worldwide, with a remarkably high incidence in the Mediterranean basin, part of Sub-Saharan Africa, the Middle East, the Indian subcontinent, and Southeast Asia. However, as the result of massive population movements, and given the chronicity of the disease and the high cost of life-long treatments, they are also becoming an important public health burden in many other European and American countries.

Historically, since the early, pioneering studies, thalassemia research has always provided inspiring lessons for discovering the complex processes and the variety of the structural elements involved in the regulation of gene expression as well as for exploring the molecular bases and the inheritance mechanisms of other human diseases. However, despite the impressive body of knowledge gathered in these decades, there is still a need for further studies in molecular genetics and clinical management that could contribute to define more effective prevention programs and support the development of novel drugs and more successful and affordable gene-therapy strategies.

To achieve these challenging targets, more in-depth knowledge is required with particular regard to the contribution of modifying factors on the clinical heterogeneity of thalassemias, the genetic control of fetal hemoglobin, the identification of novel therapeutic targets, and the advances in clinical practice leading to increase life expectancy and improve quality of life.

The purpose of this Special Issue is thus to provide novel insights and perspectives into this continually evolving topic that in the future could lead to a definitive and affordable cure for these disorders. We also hope that the research described herein can be a source of inspiration to the readers for further studies in this fascinating and not yet fully explored field.

Dr. Michela Grosso
Dr. Alexandros Makis
Guest Editors

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Keywords

thalassemia
globin gene switching
fetal hemoglobin
genetic modifiers
gene therapy
clinical management
transcriptional factors
gene silencing
genome editing
mutation detection

Published Papers (6 papers)

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Research

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Open AccessArticle

Identification and Functional Analysis of Known and New Mutations in the Transcription Factor KLF1 Linked with β-Thalassemia-like Phenotypes

and

Biology 2023, 12(4), 510; https://doi.org/10.3390/biology12040510 - 28 Mar 2023

Cited by 1 | Viewed by 705

Abstract

The erythroid transcriptional factor Krüppel-like factor 1 (KLF1) is a master regulator of erythropoiesis. Mutations that cause KLF1 haploinsufficiency have been linked to increased fetal hemoglobin (HbF) and hemoglobin A₂ (HbA₂) levels with ameliorative effects on the severity of β-thalassemia. With the aim of determining if KLF1 gene variations might play a role in the modulation of β-thalassemia, in this study we screened 17 subjects showing a β-thalassemia-like phenotype with a slight or marked increase in HbA₂ and HbF levels. Overall, seven KLF1 gene variants were identified, of which two were novel. Functional studies were performed in K562 cells to clarify the pathogenic significance of these mutations. Our study confirmed the ameliorative effect on the thalassemia phenotype for some of these variants but also raised the notion that certain mutations may have deteriorating effects by increasing KLF1 expression levels or enhancing its transcriptional activity. Our results indicate that functional studies are required to evaluate the possible effects of KLF1 mutations, particularly in the case of the co-existence of two or more mutations that could differently contribute to KLF1 expression or transcriptional activity and consequently to the thalassemia phenotype. Full article

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

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Open AccessArticle

Use of Deferasirox Film-Coated Tablets in Pediatric Patients with Transfusion Dependent Thalassemia: A Single Center Experience

Alkistis Adramerina

Nikoleta Printza

Emmanouel Hatzipantelis

and

Biology 2022, 11(2), 247; https://doi.org/10.3390/biology11020247 - 05 Feb 2022

Cited by 2 | Viewed by 1197

Abstract

Thalassemic syndromes are characterized by clinical heterogenicity. For severe disease forms, lifelong blood transfusions remain the mainstay of therapy, while iron overload monitoring and adequate chelation treatment are required in order to ensure effective disease management. Compared to previous chelators, the new deferasirox film-coated tablet (DFX FCT) is considered to offer a more convenient and well-tolerated treatment scheme, aiming at better treatment-related and patient-related outcomes. The present study’s objective was to prospectively evaluate the safety and efficacy of DFX FCT in children and adolescents with transfusion-dependent thalassemia. Data collected included patient demographics, hematology and biochemistry laboratory work up, magnetic resonance imaging of heart and liver for iron load, as well as ophthalmological and audiological examination prior to and a year following drug administration. Study results confirmed DFX FCT safety in older children in a manner similar to adults, but demonstrated increased frequency of adverse events in younger patients, mainly, involving liver function. With regards to efficacy, study results confirmed the preventive role of DFX FCT in iron loading of liver and heart, however, higher doses than generally recommended were required in order to ensure adequate chelation. Full article

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

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Open AccessArticle

Retinal and Choriocapillaris Vascular Changes in Patients Affected by Different Clinical Phenotypes of β-Thalassemia: An Optical Coherence Tomography Angiography Study

Maria Rosaria Storino

Francesca Aquila

Fausto Tranfa

and

Michela Grosso

Biology 2021, 10(4), 276; https://doi.org/10.3390/biology10040276 - 28 Mar 2021

Cited by 4 | Viewed by 1400

Abstract

In this cross-sectional study we assessed the vascular alterations in retinal and choriocapillaris perfusion in patients affected by β-thalassemia, by means of optical coherence tomography angiography (OCTA). A total of 124 eyes of 62 patients (mean age 44.74 ± 5.79 years old) affected by β-thalassemia (transfusion dependent thalassemia (TDT), non-transfusion dependent thalassemia (NTDT) and minor) were compared to 40 eyes of twenty healthy subjects. We evaluated the vessel density (VD) in superficial capillary plexus, deep capillary plexus, radial peripapillary capillary, choriocapillaris and the foveal avascular zone area. The TDT group showed a statistically significant reduction in retinal and choriocapillaris VD respect to controls and the other groups (p < 0.05). No statistically significant difference was found in OCTA parameters between β-thalassemia minor and controls. The NTDT group showed a significant reduction in VD in deep capillary plexus respect to controls and β-thalassemia minor. Significant negative correlations were shown in TDT group between foveal avascular zone and hemoglobin (r = −0.437, p = 0.044) and between ferritin levels and VD of choriocapillaris (r = −0.431, p = 0.038). The OCTA parameters provided a deeper understanding on retinal and choriocapillaris vascular impairment affected by tissue hypoxia levels and the oxidative stress in different clinical phenotypes of the β-thalassemia. Full article

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

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Review

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Open AccessReview

Gene Editing-Based Technologies for Beta-hemoglobinopathies Treatment

Shahrzad Ahangarzadeh

Yasaman Esmaeili

Elham Bidram

Golnaz Vaseghi

Shaghayegh Haghjooy Javanmard

Laleh Shariati

Ali Zarrabi

and

Rajender S. Varma

Biology 2022, 11(6), 862; https://doi.org/10.3390/biology11060862 - 04 Jun 2022

Viewed by 3028

Abstract

Beta (β)-thalassemia is a group of human inherited abnormalities caused by various molecular defects, which involves a decrease or cessation in the balanced synthesis of the β-globin chains in hemoglobin structure. Traditional treatment for β-thalassemia major is allogeneic bone marrow transplantation (BMT) from a completely matched donor. The limited number of human leukocyte antigen (HLA)-matched donors, long-term use of immunosuppressive regimen and higher risk of immunological complications have limited the application of this therapeutic approach. Furthermore, despite improvements in transfusion practices and chelation treatment, many lingering challenges have encouraged researchers to develop newer therapeutic strategies such as nanomedicine and gene editing. One of the most powerful arms of genetic manipulation is gene editing tools, including transcription activator-like effector nucleases, zinc-finger nucleases, and clustered regularly interspaced short palindromic repeat–Cas-associated nucleases. These tools have concentrated on γ- or β-globin addition, regulating the transcription factors involved in expression of endogenous γ-globin such as KLF1, silencing of γ-globin inhibitors including BCL11A, SOX6, and LRF/ZBTB7A, and gene repair strategies. In this review article, we present a systematic overview of the appliances of gene editing tools for β-thalassemia treatment and paving the way for patients’ therapy. Full article

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

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Open AccessReview

Novel Therapeutic Advances in β-Thalassemia

Alexandros Makis

Ersi Voskaridou

Ioannis Papassotiriou

and

Eleftheria Hatzimichael

Biology 2021, 10(6), 546; https://doi.org/10.3390/biology10060546 - 18 Jun 2021

Cited by 12 | Viewed by 5962

Abstract

The main characteristic of the pathophysiology of β-thalassemia is reduced β-globin chain production. The inevitable imbalance in the α/β-globin ratio and α-globin accumulation lead to oxidative stress in the erythroid lineage, apoptosis, and ineffective erythropoiesis. The result is compensatory hematopoietic expansion and impaired hepcidin production that causes increased intestinal iron absorption and progressive iron overload. Chronic hemolysis and red blood cell transfusions also contribute to iron tissue deposition. A better understanding of the underlying mechanisms led to the detection of new curative or “disease-modifying” therapeutic options. Substantial evolvement has been made in allogeneic hematopoietic stem cell transplantation with current clinical trials investigating new condition regimens as well as different donors and stem cell source options. Gene therapy has also moved forward, and phase 2 clinical trials with the use of β-globin insertion techniques have recently been successfully completed leading to approval for use in transfusion-dependent patients. Genetic and epigenetic manipulation of the γ- or β-globin gene have entered the clinical trial setting. Agents such as TGF-β ligand traps and pyruvate kinase activators, which reduce the ineffective erythropoiesis, have been tested in clinical trials with favorable results. One TGF-β ligand trap, luspatercept, has been approved for use in adults with transfusion-dependent β-thalassemia. The induction of HbF with the phosphodiesterase 9 inhibitor IMR-687, which increase cyclic guanosine monophosphate, is currently being tested. Another therapeutic approach is to target the dysregulation of iron homeostasis, using, for example, hepcidin agonists (inhibitors of TMPRSS6 and minihepcidins) or ferroportin inhibitors (VIT-2763). This review provides an update on the novel therapeutic options that are presently in development at the clinical level in β-thalassemia. Full article

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

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Open AccessBrief Report

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

Joanne Traeger-Synodinos

Christalena Sofocleous

and

Antonis Kattamis

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

Viewed by 1340

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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Special Issue "Thalassemia Research: Focus on Novel Molecular Insights and Clinical Perspectives"

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