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Blood Cells, Molecules & Diseases May 2018The remarkable phenotypic diversity of β thalassemia that range from severe anemia and transfusion-dependency, to a clinically asymptomatic state exemplifies how a... (Review)
Review
The remarkable phenotypic diversity of β thalassemia that range from severe anemia and transfusion-dependency, to a clinically asymptomatic state exemplifies how a spectrum of disease severity can be generated in single gene disorders. While the genetic basis for β thalassemia, and how severity of the anemia could be modified at different levels of its pathophysiology have been well documented, therapy remains largely supportive with bone marrow transplant being the only cure. Identification of the genetic variants modifying fetal hemoglobin (HbF) production in combination with α globin genotype provide some prediction of disease severity for β thalassemia but generation of a personalized genetic risk score to inform prognosis and guide management requires a larger panel of genetic modifiers yet to be discovered. Nonetheless, genetic studies have been successful in characterizing the key variants and pathways involved in HbF regulation, providing new therapeutic targets for HbF reactivation. BCL11A has been established as a quantitative repressor, and progress has been made in manipulating its expression using genomic and gene-editing approaches for therapeutic benefits. Recent discoveries and understanding in the mechanisms associated with ineffective and abnormal erythropoiesis have also provided additional therapeutic targets, a couple of which are currently being tested in clinical trials.
Topics: Animals; Combined Modality Therapy; Gene Expression Regulation; Genetic Association Studies; Genetic Loci; Genetic Predisposition to Disease; Genotype; Humans; Mutation; Phenotype; beta-Globins; beta-Thalassemia
PubMed: 28651846
DOI: 10.1016/j.bcmd.2017.06.001 -
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 -
Blood Mar 2023
Topics: Humans; beta-Thalassemia; Thalassemia; Mutation
PubMed: 36893006
DOI: 10.1182/blood.2022019350 -
Minerva Pediatrics Jun 2022Beta-thalassemia is a potentially lethal hereditary anemia, caused by reduced or absent expression of HBB polypeptide chains of adult hemoglobin (HbA: α2β2). Current... (Review)
Review
Beta-thalassemia is a potentially lethal hereditary anemia, caused by reduced or absent expression of HBB polypeptide chains of adult hemoglobin (HbA: α2β2). Current curative treatments options are limited to few patients, while alternative, chronic palliative therapy consisting of frequent transfusions coupled with iron chelation therapy, are costly. The above treatments also affect quality of life of patients. A search was conducted in the electronic databases like Medline, PubMed, etc. for screening studies reporting various aspects including gene therapy, prevention strategies, blood, transfusion and chelation therapy for the management of β-thalassemia. Increased levels of fetal hemoglobin (HbF: α2γ2) were shown to lessen the severity of β-thalassemia, highlighting the therapeutic potential of a gene-therapy-mediated increase in HBG1 and HBG2 (HBG) expression. The primary outcome of most of the above studies was the efficient management of β-thalassemia, without any major complication. So, the present review is focused on the recent perspectives in the management of β-thalassemia including combinatorial gene therapy for β-thalassemia.
Topics: Adult; Chelation Therapy; Child; Fetal Hemoglobin; Hemoglobin A; Humans; Quality of Life; beta-Thalassemia
PubMed: 29479942
DOI: 10.23736/S2724-5276.18.04872-7 -
Bulletin of the World Health... Jun 2008To demonstrate a method for using genetic epidemiological data to assess the needs for equitable and cost-effective services for the treatment and prevention of...
To demonstrate a method for using genetic epidemiological data to assess the needs for equitable and cost-effective services for the treatment and prevention of haemoglobin disorders. We obtained data on demographics and prevalence of gene variants responsible for haemoglobin disorders from online databases, reference resources, and published articles. A global epidemiological database for haemoglobin disorders by country was established, including five practical service indicators to express the needs for care (indicator 1) and prevention (indicators 2-5). Haemoglobin disorders present a significant health problem in 71% of 229 countries, and these 71% of countries include 89% of all births worldwide. Over 330,000 affected infants are born annually (83% sickle cell disorders, 17% thalassaemias). Haemoglobin disorders account for about 3.4% of deaths in children less than 5 years of age. Globally, around 7% of pregnant women carry b or a zero thalassaemia, or haemoglobin S, C, D Punjab or E, and over 1% of couples are at risk. Carriers and at-risk couples should be informed of their risk and the options for reducing it. Screening for haemoglobin disorders should form part of basic health services in most countries.
Topics: Anemia, Sickle Cell; Databases as Topic; Global Health; Health Services Needs and Demand; Humans; Mass Screening; beta-Thalassemia
PubMed: 18568278
DOI: 10.2471/blt.06.036673 -
British Journal of Clinical Pharmacology Aug 2022Beta-thalassaemia, including sickle cell anaemia and thalassaemia E, is most common in developing countries in tropical and subtropic regions. Because carriers have... (Review)
Review
Beta-thalassaemia, including sickle cell anaemia and thalassaemia E, is most common in developing countries in tropical and subtropic regions. Because carriers have migrated there owing to demographic migration, β-thalassaemia can now be detected in areas other than malaria-endemic areas. Every year, an estimated 300 000-500 000 infants, the vast majority of whom are from developing countries, are born with a severe haemoglobin anomaly. Currently, some basic techniques, which include iron chelation therapy, hydroxyurea, blood transfusion, splenectomy and haematopoietic stem cell transplantation, are being used to manage thalassaemia patients. Despite being the backbone of treatment, traditional techniques have several drawbacks and limitations. Ineffective erythropoiesis, correction of globin chain imbalance and adjustment of iron metabolism are some of the innovative treatment methods that have been developed in the care of thalassaemia patients in recent years. Moreover, regulating the expression of B-cell lymphoma/leukaemia 11A and sex-determining region Y-box through the enhanced expression of micro RNAs can also be considered putative targets for managing haemoglobinopathies. This review focuses on the biological basis of β-globin gene production, the pathophysiology of β-thalassaemia and the treatment options that have recently been introduced.
Topics: Blood Transfusion; Humans; Infant; Iron; Iron Chelating Agents; Thalassemia; beta-Thalassemia
PubMed: 35373382
DOI: 10.1111/bcp.15343 -
Survey of Ophthalmology 2016Patients with beta (β)-thalassemia (β-TM: β-thalassemia major, β-TI: β-thalassemia intermedia) have a variety of complications that may affect all organs, including... (Review)
Review
Patients with beta (β)-thalassemia (β-TM: β-thalassemia major, β-TI: β-thalassemia intermedia) have a variety of complications that may affect all organs, including the eye. Ocular abnormalities include retinal pigment epithelial degeneration, angioid streaks, venous tortuosity, night blindness, visual field defects, decreased visual acuity, color vision abnormalities, and acute visual loss. Patients with β-thalassemia major are transfusion dependent and require iron chelation therapy to survive. Retinal degeneration may result from either retinal iron accumulation from transfusion-induced iron overload or retinal toxicity induced by iron chelation therapy. Some who were never treated with iron chelation therapy exhibited retinopathy, and others receiving iron chelation therapy had chelator-induced retinopathy. We will focus on retinal abnormalities present in individuals with β-thalassemia major viewed in light of new findings on the mechanisms and manifestations of retinal iron toxicity.
Topics: Deferiprone; Deferoxamine; Humans; Iron Chelating Agents; Iron Overload; Pyridones; Retinal Diseases; Transfusion Reaction; beta-Thalassemia
PubMed: 26325202
DOI: 10.1016/j.survophthal.2015.08.005 -
Blood Reviews May 2023The hematologic disorders myelodysplastic syndromes and beta-thalassemia are characterized by ineffective erythropoiesis and anemia, often managed with regular blood... (Review)
Review
The hematologic disorders myelodysplastic syndromes and beta-thalassemia are characterized by ineffective erythropoiesis and anemia, often managed with regular blood transfusions. Erythropoiesis, the process by which sufficient numbers of functional erythrocytes are produced from hematopoietic stem cells, is highly regulated, and defects can negatively affect the proliferation, differentiation, and survival of erythroid precursors. Treatments that directly target the underlying mechanisms of ineffective erythropoiesis are limited, and management of anemia with regular blood transfusions imposes a significant burden on patients, caregivers, and health care systems. There is therefore a strong unmet need for treatments that can restore effective erythropoiesis. Novel therapies are beginning to address this need by targeting a variety of mechanisms underlying erythropoiesis. Herein, we provide an overview of the role of ineffective erythropoiesis in myelodysplastic syndromes and beta-thalassemia, discuss unmet needs in targeting ineffective erythropoiesis, and describe current management strategies and emerging treatments for these disorders.
Topics: Humans; beta-Thalassemia; Erythropoiesis; Erythrocytes; Hematologic Diseases; Myelodysplastic Syndromes
PubMed: 36577601
DOI: 10.1016/j.blre.2022.101039 -
Biomedical Journal Feb 2016Beta-thalassemia is a group of frequent genetic disorders resulting in the synthesis of little or no β-globin chains. Novel approaches are being developed to correct... (Review)
Review
Beta-thalassemia is a group of frequent genetic disorders resulting in the synthesis of little or no β-globin chains. Novel approaches are being developed to correct the resulting α/β-globin chain imbalance, in an effort to move beyond the palliative management of this disease and the complications of its treatment (e.g. life-long red blood cell transfusion, iron chelation, splenectomy), which impose high costs on healthcare systems. Three approaches are envisaged: fetal globin gene reactivation by pharmacological compounds injected into patients throughout their lives, allogeneic hematopoietic stem cell transplantation (HSCT), and gene therapy. HSCT is currently the only treatment shown to provide an effective, definitive cure for β-thalassemia. However, this procedure remains risky and histocompatible donors are identified for only a small fraction of patients. New pharmacological compounds are being tested, but none has yet made it into common clinical practice for the treatment of beta-thalassemia major. Gene therapy is in the experimental phase. It is emerging as a powerful approach without the immunological complications of HSCT, but with other possible drawbacks. Rapid progress is being made in this field, and long-term efficacy and safety studies are underway.
Topics: Animals; Complementary Therapies; Hematopoietic Stem Cell Transplantation; Humans; Time; Tissue Donors; Treatment Outcome; beta-Thalassemia
PubMed: 27105596
DOI: 10.1016/j.bj.2015.10.001 -
BioMed Research International 2015Thalassemia intermedia (TI), also known as nontransfusion dependent thalassemia (NTDT), is a type of thalassemia where affected patients do not require lifelong regular... (Review)
Review
Thalassemia intermedia (TI), also known as nontransfusion dependent thalassemia (NTDT), is a type of thalassemia where affected patients do not require lifelong regular transfusions for survival but may require occasional or even frequent transfusions in certain clinical settings and for defined periods of time. NTDT encompasses three distinct clinical forms: β-thalassemia intermedia (β-TI), Hb E/β-thalassemia, and α-thalassemia intermedia (Hb H disease). Over the past decade, our understanding of the molecular features, pathophysiology, and complications of NTDT particularly β-TI has increased tremendously but data on optimal treatment of disease and its various complications are still lacking. In this paper, we shall review a group of commonly encountered complications in β-TI, mainly endocrine and bone complications.
Topics: Bone and Bones; Endocrine System Diseases; Humans; beta-Thalassemia
PubMed: 25834825
DOI: 10.1155/2015/813098