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Thalassemia Research: Focus on Novel Molecular Insights and Clinical Perspectives
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Thalassemia Research: Focus on Novel Molecular Insights and Clinical Perspectives

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

Deadline for manuscript submissions: closed (20 July 2023) | Viewed by 28123

Special Issue Editors

Dr. Michela Grosso

E-Mail Website
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
Special Issues, Collections and Topics in MDPI journals
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

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Published Papers (5 papers)

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Research

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10 pages, 586 KiB  
Article
Use of Deferasirox Film-Coated Tablets in Pediatric Patients with Transfusion Dependent Thalassemia: A Single Center Experience
by Alkistis Adramerina, Nikoleta Printza, Emmanouel Hatzipantelis, Symeon Symeonidis, Labib Tarazi, Aikaterini Teli and Marina Economou
Biology 2022, 11(2), 247; https://doi.org/10.3390/biology11020247 - 5 Feb 2022
Cited by 6 | Viewed by 2462
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 [...] Read more.
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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Review

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15 pages, 2093 KiB  
Review
The Long Scientific Journey of Sirolimus (Rapamycin): From the Soil of Easter Island (Rapa Nui) to Applied Research and Clinical Trials on β-Thalassemia and Other Hemoglobinopathies
by Roberto Gambari, Cristina Zuccato, Lucia Carmela Cosenza, Matteo Zurlo, Jessica Gasparello, Alessia Finotti, Maria Rita Gamberini and Marco Prosdocimi
Biology 2023, 12(9), 1202; https://doi.org/10.3390/biology12091202 - 2 Sep 2023
Cited by 4 | Viewed by 3260
Abstract
In this review article, we present the fascinating story of rapamycin (sirolimus), a drug able to induce γ-globin gene expression and increased production of fetal hemoglobin (HbF) in erythroid cells, including primary erythroid precursor cells (ErPCs) isolated from β-thalassemia patients. For this reason, [...] Read more.
In this review article, we present the fascinating story of rapamycin (sirolimus), a drug able to induce γ-globin gene expression and increased production of fetal hemoglobin (HbF) in erythroid cells, including primary erythroid precursor cells (ErPCs) isolated from β-thalassemia patients. For this reason, rapamycin is considered of great interest for the treatment of β-thalassemia. In fact, high levels of HbF are known to be highly beneficial for β-thalassemia patients. The story of rapamycin discovery began in 1964, with METEI, the Medical Expedition to Easter Island (Rapa Nui). During this expedition, samples of the soil from different parts of the island were collected and, from this material, an antibiotic-producing microorganism (Streptomyces hygroscopicus) was identified. Rapamycin was extracted from the mycelium with organic solvents, isolated, and demonstrated to be very active as an anti-bacterial and anti-fungal agent. Later, rapamycin was demonstrated to inhibit the in vitro cell growth of tumor cell lines. More importantly, rapamycin was found to be an immunosuppressive agent applicable to prevent kidney rejection after transplantation. More recently, rapamycin was found to be a potent inducer of HbF both in vitro using ErPCs isolated from β-thalassemia patients, in vivo using experimental mice, and in patients treated with this compound. These studies were the basis for proposing clinical trials on β-thalassemia patients. Full article
(This article belongs to the Special Issue Thalassemia Research: Focus on Novel Molecular Insights and Clinical Perspectives)
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19 pages, 1972 KiB  
Review
Gene Editing-Based Technologies for Beta-hemoglobinopathies Treatment
by Ilnaz Rahimmanesh, Maryam Boshtam, Shirin Kouhpayeh, Hossein Khanahmad, Arezou Dabiri, 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 - 4 Jun 2022
Cited by 5 | Viewed by 7257
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 [...] Read more.
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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15 pages, 826 KiB  
Review
Novel Therapeutic Advances in β-Thalassemia
by 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 23 | Viewed by 10132
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 [...] Read more.
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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Other

Jump to: Research, Review

9 pages, 873 KiB  
Brief 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 2275
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, [...] Read more.
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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