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British Journal of Haematology Jul 2020Despite sickle cell disease (SCD) being the most common and severe inherited condition worldwide, therapeutic options are limited. To date, hydroxyurea remains the main... (Review)
Review
Despite sickle cell disease (SCD) being the most common and severe inherited condition worldwide, therapeutic options are limited. To date, hydroxyurea remains the main treatment option in SCD. However, in the last decade the numbers of interventional clinical trials focussing on therapies for SCD have increased significantly. Many new drugs with various pharmacological targets have emerged and, although the majority have failed to show benefit in clinical trials, some have produced encouraging results. It seems probable that more drugs will soon become available for the treatment of SCD. Furthermore, promising clinical trials with improved outcomes have recently changed the perspective of curative therapies in SCD. Nevertheless, the application of novel therapeutic agents and potential curative treatments will most likely be limited to high-income countries and, thus, will remain unavailable for the majority of people with SCD in the foreseeable future.
Topics: Anemia, Sickle Cell; Antisickling Agents; Humans; Quality of Life
PubMed: 32142156
DOI: 10.1111/bjh.16504 -
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 -
Journal of Diabetes Science and... Jan 2020
Topics: Diabetes Mellitus; Glycated Hemoglobin; Hemoglobinopathies; Humans
PubMed: 30897962
DOI: 10.1177/1932296819841698 -
The Israel Medical Association Journal... Dec 2014
Topics: Cyanosis; Diagnosis, Differential; Dyspnea; Hemoglobinopathies; Hemoglobins, Abnormal; Humans; Mutation; Oximetry; Oxygen
PubMed: 25630210
DOI: No ID Found -
Hematology/oncology and Stem Cell... Dec 2017Kuwait is located in the Arabian Gulf and has a population of 3.5million. The stem cell transplantation program started in 2000. Autologous peripheral blood stem cell... (Review)
Review
Kuwait is located in the Arabian Gulf and has a population of 3.5million. The stem cell transplantation program started in 2000. Autologous peripheral blood stem cell transplantation started first, as it was easier technically to establish. In 2011, the allogeneic program started with focus on acute leukemia and hemoglobinopathies. The success of both programs required teamwork and support of health planners. The Kuwait National Bone Marrow Registry was established in 2012. The issue of donor availability and drug shortage remain the two main obstacles for expanding the bone marrow transplantation program.
Topics: Allografts; Autografts; Bone Marrow Transplantation; Hemoglobinopathies; Humans; Kuwait; Leukemia; Peripheral Blood Stem Cell Transplantation
PubMed: 28666103
DOI: 10.1016/j.hemonc.2017.05.020 -
Hematology/oncology Clinics of North... Dec 2022Sickle cell disease (SCD) is a genetic hemoglobinopathy associated with extensive morbidity and early mortality. While there have been recent improvements in available... (Review)
Review
Sickle cell disease (SCD) is a genetic hemoglobinopathy associated with extensive morbidity and early mortality. While there have been recent improvements in available disease-modifying therapies for SCD, cardiopulmonary complications remain a major risk factor for death in this population. We provide an overview of current knowledge regarding several of the major acute and chronic cardiopulmonary complications in SCD, including: acute chest syndrome, airway disease, lung function abnormalities, nocturnal hypoxemia and sleep disordered breathing, pulmonary vascular disease, and sickle cell cardiomyopathy.
Topics: Humans; Anemia, Sickle Cell; Sleep Apnea Syndromes; Vascular Diseases
PubMed: 36400540
DOI: 10.1016/j.hoc.2022.07.014 -
Nature Medicine Mar 2015Anemia is a major source of morbidity and mortality worldwide. Here we review recent insights into how red blood cells (RBCs) are produced, the pathogenic mechanisms... (Review)
Review
Anemia is a major source of morbidity and mortality worldwide. Here we review recent insights into how red blood cells (RBCs) are produced, the pathogenic mechanisms underlying various forms of anemia, and novel therapies derived from these findings. It is likely that these new insights, mainly arising from basic scientific studies, will contribute immensely to both the understanding of frequently debilitating forms of anemia and the ability to treat affected patients. Major worldwide diseases that are likely to benefit from new advances include the hemoglobinopathies (β-thalassemia and sickle cell disease); rare genetic disorders of RBC production; and anemias associated with chronic kidney disease, inflammation, and cancer. Promising new approaches to treatment include drugs that target recently defined pathways in RBC production, iron metabolism, and fetal globin-family gene expression, as well as gene therapies that use improved viral vectors and newly developed genome editing technologies.
Topics: Anemia; Fetal Hemoglobin; Genetic Therapy; Hematinics; Hemoglobinopathies; Humans; Inflammation; Neoplasms; Renal Insufficiency, Chronic
PubMed: 25742458
DOI: 10.1038/nm.3814 -
Methods in Molecular Biology (Clifton,... 2018Animal models of erythropoiesis have been, and will continue to be, important tools for understanding molecular mechanisms underlying the development of this cell... (Review)
Review
Animal models of erythropoiesis have been, and will continue to be, important tools for understanding molecular mechanisms underlying the development of this cell lineage and the pathophysiology associated with various human erythropoietic diseases. In this regard, the mouse is probably the most valuable animal model available to investigators. The physiology and short gestational period of mice make them ideal for studying developmental processes and modeling human diseases. These attributes, coupled with cutting-edge genetic tools such as transgenesis, gene knockouts, conditional gene knockouts, and genome editing, provide a significant resource to the research community to test a plethora of hypotheses. This review summarizes the mouse models available for studying a wide variety of erythroid-related questions, as well as the properties inherent in each one.
Topics: Animals; Chromosomes, Artificial, Bacterial; Chromosomes, Artificial, Yeast; Disease Models, Animal; Erythropoiesis; Gene Expression Regulation, Developmental; Genes, Reporter; Hemoglobinopathies; Hemoglobins; Mice; Mice, Knockout; Mice, Transgenic
PubMed: 29076083
DOI: 10.1007/978-1-4939-7428-3_3 -
Genes Feb 2023Beta-like globin gene expression is developmentally regulated during life by transcription factors, chromatin looping and epigenome modifications of the β-globin locus.... (Review)
Review
Beta-like globin gene expression is developmentally regulated during life by transcription factors, chromatin looping and epigenome modifications of the β-globin locus. Epigenome modifications, such as histone methylation/demethylation and acetylation/deacetylation and DNA methylation, are associated with up- or down-regulation of gene expression. The understanding of these mechanisms and their outcome in gene expression has paved the way to the development of new therapeutic strategies for treating various diseases, such as β-hemoglobinopathies. Histone deacetylase and DNA methyl-transferase inhibitors are currently being tested in clinical trials for hemoglobinopathies patients. However, these approaches are often uncertain, non-specific and their global effect poses serious safety concerns. Epigenome editing is a recently developed and promising tool that consists of a DNA recognition domain (zinc finger, transcription activator-like effector or dead clustered regularly interspaced short palindromic repeats Cas9) fused to the catalytic domain of a chromatin-modifying enzyme. It offers a more specific targeting of disease-related genes (e.g., the ability to reactivate the fetal γ-globin genes and improve the hemoglobinopathy phenotype) and it facilitates the development of scarless gene therapy approaches. Here, we summarize the mechanisms of epigenome regulation of the β-globin locus, and we discuss the application of epigenome editing for the treatment of hemoglobinopathies.
Topics: Humans; Epigenesis, Genetic; Epigenome; Hemoglobinopathies; beta-Globins; Chromatin; DNA
PubMed: 36980849
DOI: 10.3390/genes14030577 -
Human Genetics Sep 2016Hemoglobinopathies are genetic disorders caused by aberrant hemoglobin expression or structure changes, resulting in severe mortality and health disparities worldwide.... (Review)
Review
Hemoglobinopathies are genetic disorders caused by aberrant hemoglobin expression or structure changes, resulting in severe mortality and health disparities worldwide. Sickle cell disease (SCD) and β-thalassemia, the most common forms of hemoglobinopathies, are typically treated using transfusions and pharmacological agents. Allogeneic hematopoietic stem cell transplantation is the only curative therapy, but has limited clinical applicability. Although gene therapy approaches have been proposed based on the insertion and forced expression of wild-type or anti-sickling β-globin variants, safety concerns may impede their clinical application. A novel curative approach is nuclease-based gene correction, which involves the application of precision genome-editing tools to correct the disease-causing mutation. This review describes the development and potential application of gene therapy and precision genome-editing approaches for treating SCD and β-thalassemia. The opportunities and challenges in advancing a curative therapy for hemoglobinopathies are also discussed.
Topics: Clinical Trials as Topic; Gene Editing; Genetic Therapy; Hematopoietic Stem Cell Transplantation; Hemoglobinopathies; Humans
PubMed: 27314256
DOI: 10.1007/s00439-016-1696-0