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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 -
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 -
American Family Physician Mar 2022Thalassemia is a group of autosomal recessive hemoglobinopathies affecting the production of normal alpha- or beta-globin chains that comprise hemoglobin. Ineffective...
Thalassemia is a group of autosomal recessive hemoglobinopathies affecting the production of normal alpha- or beta-globin chains that comprise hemoglobin. Ineffective production of alpha- or beta-globin chains may result in ineffective erythropoiesis, premature red blood cell destruction, and anemia. Chronic, severe anemia in patients with thalassemia may result in bone marrow expansion and extramedullary hematopoiesis. Thalassemia should be suspected in patients with microcytic anemia and normal or elevated ferritin levels. Hemoglobin electrophoresis may reveal common characteristics of different thalassemia subtypes, but genetic testing is required to confirm the diagnosis. Thalassemia is generally asymptomatic in trait and carrier states. Alpha-thalassemia major results in hydrops fetalis and is often fatal at birth. Beta-thalassemia major requires lifelong transfusions starting in early childhood (often before two years of age). Alpha- and beta-thalassemia intermedia have variable presentations based on gene mutation or deletion, with mild forms requiring only monitoring but more severe forms leading to symptomatic anemia and requiring transfusion. Treatment of thalassemia includes transfusions, iron chelation therapy to correct iron overload (from hemolytic anemia, intestinal iron absorption, and repeated transfusions), hydroxyurea, hematopoietic stem cell transplantation, and luspatercept. Thalassemia complications arise from bone marrow expansion, extramedullary hematopoiesis, and iron deposition in peripheral tissues. These complications include morbidities affecting the skeletal system, endocrine organs, heart, and liver. Life expectancy of those with thalassemia has improved dramatically over the past 50 years with increased availability of blood transfusions and iron chelation therapy, and improved iron overload monitoring. Genetic counseling and screening in high-risk populations can assist in reducing the prevalence of thalassemia.
Topics: Child, Preschool; Hematologic Diseases; Humans; Infant, Newborn; Iron; Iron Overload; Thalassemia; beta-Globins; beta-Thalassemia
PubMed: 35289581
DOI: No ID Found -
Revista Medica de Chile Sep 2021Sickle cell anemia is a type of hemoglobinopathy characterized by a specific mutation in the beta globin gene with the consequent generation of an unstable hemoglobin...
Sickle cell anemia is a type of hemoglobinopathy characterized by a specific mutation in the beta globin gene with the consequent generation of an unstable hemoglobin that crystallizes in a state of hypoxia. This causes a change in the structure of the red blood cell, which ends up producing vaso-occlusion with the corresponding clinical complications for the patient. Worldwide, various diagnostic tests have been developed that allow the appropriate approach to the affected patient. These include techniques for the determination of hemoglobin and the use of molecular markers, among others. There are new therapeutic alternatives to the use of hydroxyurea and L-glutamine, such as the use of gene therapy tools. The most recent experimental trials are exploring gene editing techniques.
Topics: Anemia, Sickle Cell; Haplotypes; Humans; Hydroxyurea; Hypoxia
PubMed: 35319686
DOI: 10.4067/S0034-98872021000901322 -
Medicine Nov 2021β-thalassemia is a hereditary hematological disease caused by over 350 mutations in the β-globin gene (HBB). Identifying the genetic variants affecting fetal... (Review)
Review
β-thalassemia is a hereditary hematological disease caused by over 350 mutations in the β-globin gene (HBB). Identifying the genetic variants affecting fetal hemoglobin (HbF) production combined with the α-globin genotype provides some prediction of disease severity for β-thalassemia. However, the generation of an additive composite genetic risk score predicts prognosis, and guide management requires a larger panel of genetic modifiers yet to be discovered.Presently, using data from prior clinical trials guides the design of further research and academic studies based on gene augmentation, while fundamental insights into globin switching and new technology developments have inspired the investigation of novel gene therapy approaches.Genetic studies have successfully characterized the causal variants and pathways involved in HbF regulation, providing novel therapeutic targets for HbF reactivation. In addition to these HBB mutation-independent strategies involving HbF synthesis de-repression, the expanding genome editing toolkit provides increased accuracy to HBB mutation-specific strategies encompassing adult hemoglobin restoration for personalized treatment of hemoglobinopathies. Allogeneic hematopoietic stem cell transplantation was, until very recently, the curative option available for patients with transfusion-dependent β-thalassemia. Gene therapy currently represents a novel therapeutic promise after many years of extensive preclinical research to optimize gene transfer protocols.We summarize the current state of developments in the molecular genetics of β-thalassemia over the last decade, including the mechanisms associated with ineffective erythropoiesis, which have also provided valid therapeutic targets, some of which have been shown as a proof-of-concept.
Topics: Fetal Hemoglobin; Gene Editing; Hemoglobinopathies; Humans; Molecular Biology; beta-Thalassemia
PubMed: 34766559
DOI: 10.1097/MD.0000000000027522 -
International Journal of Molecular... May 2023Beta-hemoglobinopathies are the most common genetic disorders worldwide, caused by a wide spectrum of mutations in the β-globin locus, and associated with morbidity and... (Review)
Review
Beta-hemoglobinopathies are the most common genetic disorders worldwide, caused by a wide spectrum of mutations in the β-globin locus, and associated with morbidity and early mortality in case of patient non-adherence to supportive treatment. Allogeneic transplantation of hematopoietic stem cells (allo-HSCT) used to be the only curative option, although the indispensable need for an HLA-matched donor markedly restricted its universal application. The evolution of gene therapy approaches made possible the ex vivo delivery of a therapeutic β- or γ- globin gene into patient-derived hematopoietic stem cells followed by the transplantation of corrected cells into myeloablated patients, having led to high rates of transfusion independence (thalassemia) or complete resolution of painful crises (sickle cell disease-SCD). Hereditary persistence of fetal hemoglobin (HPFH), a syndrome characterized by increased γ-globin levels, when co-inherited with β-thalassemia or SCD, converts hemoglobinopathies to a benign condition with mild clinical phenotype. The rapid development of precise genome editing tools (ZFN, TALENs, CRISPR/Cas9) over the last decade has allowed the targeted introduction of mutations, resulting in disease-modifying outcomes. In this context, genome editing tools have successfully been used for the introduction of HPFH-like mutations both in promoters or/and in the erythroid enhancer of to increase HbF expression as an alternative curative approach for β-hemoglobinopathies. The current investigation of new HbF modulators, such as ZBTB7A, KLF-1, SOX6, and ZNF410, further expands the range of possible genome editing targets. Importantly, genome editing approaches have recently reached clinical translation in trials investigating HbF reactivation in both SCD and thalassemic patients. Showing promising outcomes, these approaches are yet to be confirmed in long-term follow-up studies.
Topics: Humans; CRISPR-Cas Systems; Cell Line, Tumor; Transcription Factors; DNA-Binding Proteins; Hemoglobinopathies; Gene Editing; Anemia, Sickle Cell; gamma-Globins; beta-Thalassemia
PubMed: 37298481
DOI: 10.3390/ijms24119527 -
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 -
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 -
Hemoglobin Jan 2022For an archipelago that has a rich history of trade with overseas merchants and colonial rule, the Philippine Islands are models of ethnic and cultural diversity,... (Review)
Review
For an archipelago that has a rich history of trade with overseas merchants and colonial rule, the Philippine Islands are models of ethnic and cultural diversity, including hereditary blood disorders such as hemoglobinopathies. Pending a government-led comprehensive national screening program, available cluster data provides evidence of the prevalence of thalassemia in the country. The National Blood Services Act of 1994 was enacted to promote voluntary blood donation to address the supply of blood products but falls short in addressing the immense blood transfusion requirements of the thalassemic community. Iron overload monitoring and management is a considerable challenge due to high cost of laboratory tests and iron chelators on top of minimal health insurance coverage for the majority of Filipino patients with thalassemia. Continuous engagement with the thalassemia patient community and multi sectoral efforts are the means to ensure sustained improvement in the delivery of care.
Topics: Hemoglobinopathies; Humans; Iron Chelating Agents; Iron Overload; Philippines; Thalassemia
PubMed: 35950581
DOI: 10.1080/03630269.2021.2023566 -
Hemoglobin Jan 2022Management and control of hemoglobinopathies are a challenge in India where 67.0% of people reside in rural regions. The GDP spent on health is one of the lowest (1.3%)... (Review)
Review
Management and control of hemoglobinopathies are a challenge in India where 67.0% of people reside in rural regions. The GDP spent on health is one of the lowest (1.3%) resulting in high out-of-pocket expenses. The β-thalassemias are prevalent with an estimated 7500-12000 new births each year. Hb S (: c.20A>T) and Hb E (: c.79G>A) are also common regionally. Over 80 β-thalassemia (β-thal) mutations have been characterized in Indians. The δ gene mutations are increasingly being described and their coinheritance in β-thal carriers leads to a reduction in Hb A levels and a misdiagnosis of carriers. Around 15-20 centers offer prenatal diagnosis (PND) mainly in urban regions. The projected annual cost of care of β-thal patients over a decade (2016-2026) will increase from INR30,000 (US$448) million to INR55,000 (US$820) million if all patients are adequately treated. Cost comparisons are difficult to make with other international studies as the standard of care, cost of medicines and other services vary in different countries. Several centers provide hematopoietic stem cell transplants (HSCTs) for thalassemias, however, only around 250 HSCTs are done annually. Although the cost is high, financial assistance is available for a few patients. There are disparities in the quality of care and to address this a National Policy has been proposed for the management and prevention of hemoglobinopathies that will embark on a comprehensive program, providing adequate care and augmenting the existing public health care services. It will also include training, genetic counseling and easier access to preventive options and a National Registry.
Topics: Female; Hemoglobinopathies; Heterozygote; Humans; India; Mutation; Pregnancy; Thalassemia; beta-Thalassemia
PubMed: 35950587
DOI: 10.1080/03630269.2021.2008958