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British Journal of Clinical Pharmacology Jun 2022Beta-thalassaemia is one of the most significant haemoglobinopathies worldwide resulting in the synthesis of little or no β-globin chains. Without treatment,... (Review)
Review
Beta-thalassaemia is one of the most significant haemoglobinopathies worldwide resulting in the synthesis of little or no β-globin chains. Without treatment, β-thalassaemia major is lethal within the first decade of life due to the complex pathophysiology, which leads to wide clinical manifestations. Current clinical management for these patients depends on repeated transfusions followed by iron-chelating therapy. Several novel approaches to correct the resulting α/β-globin chain imbalance, treat ineffective erythropoiesis and improve iron overload are currently being developed. Up to now, the only curative treatment for β-thalassemia is haematopoietic stem-cell transplantation, but this is a risky and costly procedure. Gene therapy, gene editing and base editing are emerging as a powerful approach to treat this disease. In β-thalassaemia, gene therapy involves the insertion of a vector containing the normal β-globin or γ-globin gene into haematopoietic stem cells to permanently produce normal red blood cells. Gene editing and base editing involves the use of zinc finger nucleases, transcription activator-like nucleases and clustered regularly interspaced short palindromic repeats/Cas9 to either correct the causative mutation or else insert a single nucleotide variant that will increase foetal haemoglobin. In this review, we will examine the current management strategies used to treat β-thalassaemia and focus on the novel therapies targeting ineffective erythropoiesis, improving iron overload and correction of the globin chain imbalance.
Topics: Hematopoietic Stem Cell Transplantation; Humans; Iron Chelating Agents; Iron Overload; beta-Globins; beta-Thalassemia
PubMed: 34004015
DOI: 10.1111/bcp.14918 -
Med (New York, N.Y.) Feb 2021Studies of the major hemoglobin disorders, β-thalassemia and sickle cell disease (SCD), have laid a foundation for molecular medicine. While enormous progress has been... (Review)
Review
Studies of the major hemoglobin disorders, β-thalassemia and sickle cell disease (SCD), have laid a foundation for molecular medicine. While enormous progress has been made in understanding gene structure and regulation, translating molecular insights to therapy for the many individuals affected with these disorders has been challenging. Advances in three activities have recently converged to bring novel genetic and potentially curative treatments to clinical trials. First, improved lentiviral vectors for gene transfer into hematopoietic stem cells have revived somatic gene therapy for blood disorders. Second, elucidation of regulatory factors and mechanisms that control the normal developmental switch from fetal to adult hemoglobin has provided a route to reactivation of the fetal form for therapy. Third, revolutionary methods of gene engineering permit molecular insights to be leveraged for patients. Here I review how the promise of molecular medicine to bring transformative treatments to the clinical arena is finally being realized.
Topics: Adult; Genetic Therapy; Hemoglobinopathies; Hemoglobins; Humans; Molecular Medicine; beta-Thalassemia
PubMed: 33688634
DOI: 10.1016/j.medj.2020.12.011 -
International Journal of Molecular... Nov 2023Hemoglobinopathies, including β-thalassemia and sickle cell disease (SCD), are common genetic blood disorders. Endocrine disorders are frequent manifestations of organ... (Review)
Review
Hemoglobinopathies, including β-thalassemia and sickle cell disease (SCD), are common genetic blood disorders. Endocrine disorders are frequent manifestations of organ damage observed mainly in patients with β-thalassemia and rarely in SCD. Iron overload, oxidative stress-induced cellular damage, chronic anemia, and HCV infection contribute to the development of endocrinopathies in β-thalassemia. The above factors, combined with vaso-occlusive events and microcirculation defects, are crucial for endocrine dysfunction in SCD patients. These endocrinopathies include diabetes mellitus, hypothyroidism, parathyroid dysfunction, gonadal and growth failure, osteoporosis, and adrenal insufficiency, affecting the quality of life of these patients. Thus, we aim to provide current knowledge and data about the epidemiology, pathogenesis, diagnosis, and management of endocrine disorders in β-thalassemia and SCD. We conducted a comprehensive review of the literature and examined the available data, mostly using the PubMed and Medline search engines for original articles. In the era of precision medicine, more studies investigating the potential role of genetic modifiers in the development of endocrinopathies in hemoglobinopathies are essential.
Topics: Humans; Iron; beta-Thalassemia; Quality of Life; Hemoglobinopathies; Anemia, Sickle Cell; Diabetes Mellitus
PubMed: 38003451
DOI: 10.3390/ijms242216263 -
Acta Bio-medica : Atenei Parmensis Sep 2021Starting from 2021, Acta Biomedica Parmensis will dedicate an annual update to the "Advances in Hemoglobinopathies". The section editor of this new editorial initiative...
Starting from 2021, Acta Biomedica Parmensis will dedicate an annual update to the "Advances in Hemoglobinopathies". The section editor of this new editorial initiative is prof. Ashraf T Soliman, Pediatrician and Endocrinologist at Hamad Medical Center (HMC) of Doha. Prof Soliman is a pionier in the study of endocrine complications in hemoglobinopathies and effects of blood transfusions on spermatogenesis. He collaborates strictly with prof. Mohamed Yassin, Hematologist-Oncologist at MCH and the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescence Medicine (ICET-A). This issue of Acta Biomedica contains three articles on: The different patterns of insulin response during Oral Glucose Tolerance Test (OGTT) in transfused young patients with β- Thalassemia; Immigration and screening programs for hemoglobinopathies in Italy, Spain and Turkey and The effects of treatment with blood transfusion, iron chelation and hydroxyurea on puberty, growth and spermatogenesis in sickle cell disease,.
Topics: Anemia, Sickle Cell; Emigration and Immigration; Hemoglobinopathies; Humans; Male; Thalassemia; beta-Thalassemia
PubMed: 34487058
DOI: 10.23750/abm.v92i4.11927 -
Blood Sep 2022
Topics: Anemia, Sickle Cell; Child; Hemoglobinopathies; Humans; Ticagrelor
PubMed: 36173660
DOI: 10.1182/blood.2022017213 -
Blood Cells, Molecules & Diseases May 2018
Topics: Animals; Genetic Association Studies; Genetic Predisposition to Disease; Globins; Hemoglobinopathies; Humans
PubMed: 28214138
DOI: 10.1016/j.bcmd.2017.02.002 -
Human Genomics Jun 2021For decades, various strategies have been proposed to solve the enigma of hemoglobinopathies, especially severe cases. However, most of them seem to be lagging in terms... (Review)
Review
For decades, various strategies have been proposed to solve the enigma of hemoglobinopathies, especially severe cases. However, most of them seem to be lagging in terms of effectiveness and safety. So far, the most prevalent and promising treatment options for patients with β-types hemoglobinopathies, among others, predominantly include drug treatment and gene therapy. Despite the significant improvements of such interventions to the patient's quality of life, a variable response has been demonstrated among different groups of patients and populations. This is essentially due to the complexity of the disease and other genetic factors. In recent years, a more in-depth understanding of the molecular basis of the β-type hemoglobinopathies has led to significant upgrades to the current technologies, as well as the addition of new ones attempting to elucidate these barriers. Therefore, the purpose of this article is to shed light on pharmacogenomics, gene addition, and genome editing technologies, and consequently, their potential use as direct and indirect genome-based interventions, in different strategies, referring to drug and gene therapy. Furthermore, all the latest progress, updates, and scientific achievements for patients with β-type hemoglobinopathies will be described in detail.
Topics: Anemia, Sickle Cell; Gene Editing; Genetic Therapy; Hemoglobinopathies; Humans; beta-Globins; beta-Thalassemia
PubMed: 34090531
DOI: 10.1186/s40246-021-00329-0 -
The Lancet. Global Health Jan 2022
Topics: Developing Countries; Hemoglobin, Sickle; Hemoglobinopathies; Humans; Infant, Newborn; Neonatal Screening
PubMed: 34919844
DOI: 10.1016/S2214-109X(21)00559-3 -
American Journal of Hematology Jan 2020
Topics: Humans; beta-Thalassemia; delta-Thalassemia
PubMed: 31444804
DOI: 10.1002/ajh.25623 -
Gene Jul 2018MYB is a transcription factor which was identified in birds as a viral oncogene (v-MYB). Its cellular counterpart was subsequently isolated as c-MYB which has three... (Review)
Review
MYB is a transcription factor which was identified in birds as a viral oncogene (v-MYB). Its cellular counterpart was subsequently isolated as c-MYB which has three functional domains - DNA binding domain, transactivation domain and negative regulatory domain. c-MYB is essential for survival, and deletion of both alleles of the gene results in embryonic death. It is highly expressed in hematopoietic cells, thymus and neural tissue, and required for T and B lymphocyte development and erythroid maturation. Additionally, aberrant MYB expression has been found in numerous solid cancer cells and human leukemia. Recent studies have also implicated c-MYB in the regulation of expression of fetal hemoglobin which is highly beneficial to the β-hemoglobinopathies (beta thalassemia and sickle cell disease). These findings suggest that MYB could be a potential therapeutic target in leukemia, and possibly also a target for therapeutic increase of fetal hemoglobin in the β-hemoglobinopathies.
Topics: Anemia, Sickle Cell; Animals; Fetal Hemoglobin; Gene Expression Regulation; Hematopoiesis; Humans; Proto-Oncogene Proteins c-myb; beta-Thalassemia
PubMed: 29704633
DOI: 10.1016/j.gene.2018.04.065