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Hematology/oncology Clinics of North... Aug 2022β-thalassemia and sickle cell disease (SCD) are the most common monogenic diseases in the world and are potentially curable after allogeneic hematopoietic stem cell... (Review)
Review
β-thalassemia and sickle cell disease (SCD) are the most common monogenic diseases in the world and are potentially curable after allogeneic hematopoietic stem cell transplantation (HSCT) or autologous HSCT after genetic modification. Autologous gene therapy has the potential to offer a universal cure that overcomes many limitations of allogeneic HSCT including the lack of available donors, graft-vs-host disease, and graft rejection. Significant progress in gene therapy for the hemoglobinopathies has been made over the last several decades, now with multiple ongoing clinical trials investigating both gene addition and gene-editing strategies. Available results from a small number of patients, some with relatively short follow-up, are promising, with current efforts focused on continuing to improve the efficacy, durability, and safety of gene therapies for the cure of hemoglobin disorders.
Topics: Anemia, Sickle Cell; Genetic Therapy; Hematopoietic Stem Cell Transplantation; Hemoglobinopathies; Humans; beta-Thalassemia
PubMed: 35773052
DOI: 10.1016/j.hoc.2022.03.008 -
Australian Journal of General Practice Mar 2019Anaemia in pregnancy is a common medical condition managed by general practitioners (GPs) in Australia.
BACKGROUND
Anaemia in pregnancy is a common medical condition managed by general practitioners (GPs) in Australia.
OBJECTIVE
The aim of this article is to raise awareness of anaemia that occurs in pregnancy, understand its increasing complexities with an expanding migrant population, identify at-risk groups and promote appropriate management.
DISCUSSION
With anaemia reportedly occurring in 25% of women in pregnancy and GPs managing the majority of preconception and early pregnancy care, it is important to have a sound understanding of the aetiology, risks and management options. While iron deficiency anaemia is most commonly seen, a more complex understanding in regard to other causes and haemoglobinopathy screening is required.
Topics: Adult; Anemia; Anemia, Iron-Deficiency; Australia; Avitaminosis; Female; Helminthiasis; Hemoglobinopathies; Humans; Iron; Iron Deficiencies; Mass Screening; Pregnancy; Pregnancy Complications; Prenatal Care
PubMed: 31256475
DOI: 10.31128/AJGP-08-18-4664 -
Hemoglobin Jan 2022India bears a huge burden of hemoglobinopathies, and the most prevalent is thalassemia. The different types of thalassemia include minor, major and intermedia, based on... (Review)
Review
India bears a huge burden of hemoglobinopathies, and the most prevalent is thalassemia. The different types of thalassemia include minor, major and intermedia, based on the α/β-globin chain inequality. This review aimed to understand the current prevalence of thalassemia in different regions of India and communities affected by it, along with the management of β-thalassemia major (β-TM) and β-thalassemia (β-thal) minor patients. A comprehensive electronic search for relevant articles was conducted using two databases, PubMed and Science Direct. Articles published in English from India between January 2009 and September 2021 were included. Studies from other countries, genetic and molecular characterization studies, and articles published in other languages were excluded. The prevalence of β-thal trait in Central India ranged between 1.4 and 3.4%, while 0.94% β-TM was reported among the patients with anemia. In South India, the prevalence of β-thal trait was between 8.50 and 37.90% and β-TM was reported to be between 2.30 and 7.47%. Northern and Western Indian states had a higher thalassemic burden. In Eastern India, tribal populations had a higher prevalence of β-thal trait (0.00-30.50%), β-TM (0.36-13.20%) and other hemoglobinopathies [Hb E (: c.79G>A)/β-thal] (0.04-15.45%) than nontribal populations. Additionally, scheduled castes, scheduled tribes and other backward classes of low socioeconomic status and low literacy rates were affected by β-thal. Almost all Indian states reported β-thal; however, it is mostly concentrated in eastern and western parts of the country. Well-integrated strategies and effective implementation are needed at State and National levels to minimize the burden of β-thal.
Topics: Hemoglobinopathies; Humans; India; Mutation; Prevalence; alpha-Thalassemia; beta-Globins; beta-Thalassemia
PubMed: 35129043
DOI: 10.1080/03630269.2021.2001346 -
Indian Journal of Pediatrics Jan 2020Hemolytic anemias are a group of disorders with varied clinical and molecular heterogeneity. They are characterized by decreased levels of circulating erythrocytes in... (Review)
Review
Hemolytic anemias are a group of disorders with varied clinical and molecular heterogeneity. They are characterized by decreased levels of circulating erythrocytes in blood. The pathognomic finding is a reduced red cell life span with severe anemia or, compensated hemolysis accompanied by reticulocytosis. The diagnostic workup or laboratory approach for hemolytic anemias is based on methodical step-wise testing which includes red blood cell morphology, hematological indices with increased reticulocyte count along with clinical features of hemolytic anemias. If conventional laboratory tests are unable to detect the underlying cause of hemolysis, genetic testing is recommended. Sanger sequencing along with conventional testing is the most efficient way to diagnose the underlying genetic causes, especially in thalassemias/hemoglobinopathies, if required. However, hemolytic anemias being highly heterogeneous disorders, next-generation sequencing-based screening is rapidly becoming an efficient way to decipher the etiologies where common causes have been excluded.
Topics: Anemia, Hemolytic; Anemia, Hemolytic, Congenital Nonspherocytic; Clinical Laboratory Techniques; Elliptocytosis, Hereditary; Erythrocytes; Genetic Testing; Glucosephosphate Dehydrogenase Deficiency; Hematologic Tests; Hemoglobinopathies; Hemoglobinuria, Paroxysmal; Hemolysis; High-Throughput Nucleotide Sequencing; Humans; Pyruvate Kinase; Pyruvate Metabolism, Inborn Errors; Reticulocyte Count; Spherocytosis, Hereditary; Thalassemia
PubMed: 31823208
DOI: 10.1007/s12098-019-03119-8 -
International Journal of Laboratory... Sep 2022Hemoglobinopathies are the most common monogenic disorders in the world with an ever increasing global disease burden each year. As most hemoglobinopathies show... (Review)
Review
Hemoglobinopathies are the most common monogenic disorders in the world with an ever increasing global disease burden each year. As most hemoglobinopathies show recessive inheritance carriers are usually clinically silent. Programmes for preconception and antenatal carrier screening, with the option of prenatal diagnosis are considered beneficial in many endemic countries. With the development of genetic tools such as Array analysis and Next Generation Sequencing in addition to state of the art screening at the hematologic, biochemic and genetic level, have contributed to the discovery of an increasing number of rare rearrangements and novel factors influencing the disease severity over the recent years. This review summarizes the basic requirements for adequate carrier screening analysis, the importance of genotype-phenotype correlation and how this may lead to the unrevealing exceptional interactions causing a clinically more severe phenotype in otherwise asymptomatic carriers. A special group of patients are β-thalassemia carriers presenting with features of β-thalassemia intermedia of various clinical severity. The disease mechanisms may involve duplicated α-globin genes, mosaic partial Uniparental Isodisomy of chromosome 11p15.4 where the HBB gene is located or haplo-insufficiency of a non-linked gene SUPT5H on chromosome 19q, first described in two Dutch families with β-thalassemia trait without variants in the HBB gene.
Topics: Female; Genotype; Hemoglobinopathies; Humans; Nuclear Proteins; Phenotype; Pregnancy; Prenatal Diagnosis; Transcriptional Elongation Factors; alpha-Globins; beta-Thalassemia
PubMed: 36074711
DOI: 10.1111/ijlh.13885 -
Viruses Mar 2023Investigations to understand the function and control of the globin genes have led to some of the most exciting molecular discoveries and biomedical breakthroughs of the... (Review)
Review
Investigations to understand the function and control of the globin genes have led to some of the most exciting molecular discoveries and biomedical breakthroughs of the 20th and 21st centuries. Extensive characterization of the globin gene locus, accompanied by pioneering work on the utilization of viruses as human gene delivery tools in human hematopoietic stem and progenitor cells (HPSCs), has led to transformative and successful therapies via autologous hematopoietic stem-cell transplant with gene therapy (HSCT-GT). Due to the advanced understanding of the β-globin gene cluster, the first diseases considered for autologous HSCT-GT were two prevalent β-hemoglobinopathies: sickle cell disease and β-thalassemia, both affecting functional β-globin chains and leading to substantial morbidity. Both conditions are suitable for allogeneic HSCT; however, this therapy comes with serious risks and is most effective using an HLA-matched family donor (which is not available for most patients) to obtain optimal therapeutic and safe benefits. Transplants from unrelated or haplo-identical donors carry higher risks, although they are progressively improving. Conversely, HSCT-GT utilizes the patient's own HSPCs, broadening access to more patients. Several gene therapy clinical trials have been reported to have achieved significant disease improvement, and more are underway. Based on the safety and the therapeutic success of autologous HSCT-GT, the U.S. Food and Drug Administration (FDA) in 2022 approved an HSCT-GT for β-thalassemia (Zynteglo™). This review illuminates the β-globin gene research journey, adversities faced, and achievements reached; it highlights important molecular and genetic findings of the β-globin locus, describes the predominant globin vectors, and concludes by describing promising results from clinical trials for both sickle cell disease and β-thalassemia.
Topics: Humans; beta-Thalassemia; Hematopoietic Stem Cell Transplantation; Genetic Vectors; Hemoglobinopathies; Anemia, Sickle Cell; Genetic Therapy; beta-Globins
PubMed: 36992422
DOI: 10.3390/v15030713 -
Progress in Molecular Biology and... 2021β-hemoglobinopathies are the most common monogenic disorders worldwide and are caused by mutations in the β-globin locus altering the production of adult hemoglobin...
β-hemoglobinopathies are the most common monogenic disorders worldwide and are caused by mutations in the β-globin locus altering the production of adult hemoglobin (HbA). Transplantation of autologous hematopoietic stem cells (HSCs) corrected by lentiviral vector-mediated addition of a functional β-like globin raised new hopes to treat sickle cell disease and β-thalassemia patients; however, the low expression of the therapeutic gene per vector copy is often not sufficient to fully correct the patients with a severe clinical phenotype. Recent advances in the genome editing field brought new possibilities to cure β-hemoglobinopathies by allowing the direct modification of specific endogenous loci. Double-strand breaks (DSBs)-inducing nucleases (i.e., ZFNs, TALENs and CRISPR-Cas9) or DSB-free tools (i.e., base and prime editing) have been used to directly correct the disease-causing mutations, restoring HbA expression, or to reactivate the expression of the fetal hemoglobin (HbF), which is known to alleviate clinical symptoms of β-hemoglobinopathy patients. Here, we describe the different genome editing tools, their application to develop therapeutic approaches to β-hemoglobinopathies and ongoing clinical trials using genome editing strategies.
Topics: Fetal Hemoglobin; Gene Editing; Hemoglobinopathies; Humans; beta-Globins; beta-Thalassemia
PubMed: 34175041
DOI: 10.1016/bs.pmbts.2021.01.025 -
European Journal of Pediatrics Jun 2023Hemoglobinopathies, including thalassemias and sickle cell disease, are the most common monogenic diseases worldwide, with estimated annual births of more than 330,000... (Review)
Review
Hemoglobinopathies, including thalassemias and sickle cell disease, are the most common monogenic diseases worldwide, with estimated annual births of more than 330,000 affected infants. Hemoglobin disorders account for about 3.4% of deaths in children under 5 years of age. The distribution of these diseases is historically linked to current or previously malaria-endemic regions; however, immigration has led to a worldwide distribution of these diseases, making them a global health problem. During the last decade, new treatment approaches and novel therapies have been proposed, some of which have the potential to change the natural history of these disorders. Indeed, the first erythroid maturation agent, luspatercept, and gene therapy have been approved for beta-thalassemia adult patients. For sickle cell disease, molecules targeting vaso-occlusion and hemoglobin S polymerization include crizanlizumab, which has been approved for patients ≥ 16 years, voxelotor approved for patients ≥ 12 years, and L-glutamine for patients older than 5 years. Conclusion: We herein present the most recent advances and future perspectives in thalassemia and sickle cell disease treatment, including new drugs, gene therapy, and gene editing, and the current clinical trial status in the pediatric populations. What is Known: • Red blood cell transfusions, iron chelation therapy and hematopoietic stem cell transplantation have been the mainstay of treatment of thalassemia patients for decades. • For sickle cell disease, until 2005, treatment strategies were mostly the same as those for thalassemia, with the option of simple transfusion or exchange transfusion. In 2007, hydroxyurea was approved for patients ≥ 2 years old. What is New: • In 2019, gene therapy with betibeglogene autotemcel (LentiGlobin BB305) was approved for TDT patients ≥ 12 years old non β0/β0 without matched sibling donor. • Starting from 2017 several new drugs, such as L-glutamine (approved only by FDA), crizanlizumab (approved by FDA and EMA for patients ≥ 16 years), and lastly voxelotor (approved by FDA and EMA for patients ≥ 12 years old).
Topics: Infant; Child; Humans; Young Adult; Child, Preschool; Glutamine; Anemia, Sickle Cell; Hemoglobinopathies; Thalassemia
PubMed: 36997768
DOI: 10.1007/s00431-023-04900-w -
Hemoglobin Jan 2022The population of Viet Nam, is 96.2 million, of which 13.8% are carriers of thalassemia genes. Thalassemia/hemoglobinopathies carriers exist at different frequencies in... (Review)
Review
The population of Viet Nam, is 96.2 million, of which 13.8% are carriers of thalassemia genes. Thalassemia/hemoglobinopathies carriers exist at different frequencies in all 54 ethnic groups of the country. Gene carrier rate and globin gene mutation rate varies ethnically and topographically. The ethnic groups in the Northern Highland region have high rates of α- and β-thalassemia (α- and β-thal), while those in the Southern Middle region have high rates of α-thalassemia (α-thal) and Hb E (or codon 26) (: c.79G>A). The lowest is found in La Hu (0.23%), while the highest is found in Raglai (88.6%). Thalassemia prevention and control programs were introduced using prenatal and neonatal diagnosis for the prevention of new thalassemic births. Most existing thalassemia patients are undergoing supportive treatment with regular blood transfusions and iron chelation. Curative treatment by hematopoietic stem cell transplantation is available but is limited to a minority of the patients.
Topics: Female; Genotype; Hemoglobinopathies; Heterozygote; Humans; Infant, Newborn; Mutation; Pregnancy; Vietnam; alpha-Thalassemia; beta-Thalassemia
PubMed: 35950578
DOI: 10.1080/03630269.2022.2069032 -
Human Gene Therapy Sep 2023β-Thalassemia and sickle cell disease are autosomal recessive disorders of red blood cells due to mutations in the adult β-globin gene, with a worldwide diffusion. The... (Review)
Review
β-Thalassemia and sickle cell disease are autosomal recessive disorders of red blood cells due to mutations in the adult β-globin gene, with a worldwide diffusion. The severe forms of hemoglobinopathies are fatal if untreated, and allogeneic bone marrow transplantation can be offered to a limited proportion of patients. The unmet clinical need and the disease incidence have promoted the development of new genetic therapies based on the engineering of autologous hematopoietic stem cells. Here, the steps of gene therapy development are reviewed along with results from clinical trials and recent new approaches employing cutting edge gene editing tools.
Topics: Adult; Humans; Hemoglobinopathies; Anemia, Sickle Cell; beta-Thalassemia; Genetic Therapy; Gene Editing
PubMed: 37675899
DOI: 10.1089/hum.2023.138