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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 -
JCI Insight Oct 2022Individuals with β-thalassemia or sickle cell disease and hereditary persistence of fetal hemoglobin (HPFH) possessing 30% fetal hemoglobin (HbF) appear to be symptom...
Individuals with β-thalassemia or sickle cell disease and hereditary persistence of fetal hemoglobin (HPFH) possessing 30% fetal hemoglobin (HbF) appear to be symptom free. Here, we used a nonintegrating HDAd5/35++ vector expressing a highly efficient and accurate version of an adenine base editor (ABE8e) to install, in vivo, a -113 A>G HPFH mutation in the γ-globin promoters in healthy CD46/β-YAC mice carrying the human β-globin locus. Our in vivo hematopoietic stem cell (HSC) editing/selection strategy involves only s.c. and i.v. injections and does not require myeloablation and HSC transplantation. In vivo HSC base editing in CD46/β-YAC mice resulted in > 60% -113 A>G conversion, with 30% γ-globin of β-globin expressed in 70% of erythrocytes. Importantly, no off-target editing at sites predicted by CIRCLE-Seq or in silico was detected. Furthermore, no critical alterations in the transcriptome of in vivo edited mice were found by RNA-Seq. In vitro, in HSCs from β-thalassemia and patients with sickle cell disease, transduction with the base editor vector mediated efficient -113 A>G conversion and reactivation of γ-globin expression with subsequent phenotypic correction of erythroid cells. Because our in vivo base editing strategy is safe and technically simple, it has the potential for clinical application in developing countries where hemoglobinopathies are prevalent.
Topics: Adenine; Anemia, Sickle Cell; Animals; CRISPR-Cas Systems; Fetal Hemoglobin; Gene Editing; Hemoglobinopathies; Humans; Mice; beta-Globins; beta-Thalassemia; gamma-Globins
PubMed: 36006707
DOI: 10.1172/jci.insight.162939 -
British Medical Journal May 1973
Topics: Africa; Anemia, Sickle Cell; Hemoglobinopathies; History, 20th Century
PubMed: 4574352
DOI: 10.1136/bmj.2.5861.304 -
European Journal of Heart Failure Apr 2017Hereditary haemoglobinopathies, mainly beta-thalassemia and sickle cell disease, constitute the most common monogenic disorders in humans, and although once... (Review)
Review
Hereditary haemoglobinopathies, mainly beta-thalassemia and sickle cell disease, constitute the most common monogenic disorders in humans, and although once geographically confined, they are currently globally distributed. They are demanding clinical entities that require multidisciplinary medical management. Despite their genotypic and phenotypic heterogeneity, the haemoglobinopathies share several similarities in pathophysiology, clinical manifestations, therapeutic requirements, and complications, among which heart failure (HF) represents a leading cause of mortality and morbidity. However, haemoglobinopathies have generally been addressed in a rather fragmentary manner. A unifying approach focusing on the underlying similarities of HF attributes in the two main entities might contribute to their better understanding, characterization, and management. In the present review, we attempt such an approach to the pathophysiology, clinical phenotypes, and management of HF in haemoglobinopathies.
Topics: Anemia, Sickle Cell; Blood Transfusion; Cardiac Output; Heart Failure; Heart Valve Diseases; Hemoglobinopathies; Humans; Hypertension, Pulmonary; Iron Overload; Myocardial Ischemia; Transfusion Reaction; Vascular Diseases; Ventricular Dysfunction, Left; Ventricular Dysfunction, Right; beta-Thalassemia
PubMed: 28000341
DOI: 10.1002/ejhf.708 -
British Journal of Haematology Nov 2019Sickle cell disease (SCD) and thalassaemia are genetic disorders that are caused by errors in the genes for haemoglobin and are some of the most common significant... (Review)
Review
Sickle cell disease (SCD) and thalassaemia are genetic disorders that are caused by errors in the genes for haemoglobin and are some of the most common significant genetic disorders in the world, resulting in significant morbidity and mortality. Great disparities exist in the outcome of these conditions between resource- rich and resource-poor nations. Antenatal screening for these disorders aims to provide couples with information about their reproductive risk and enable them to make informed reproductive choices; ultimately reducing the likelihood of children being born with these conditions. This review provides an overview of the current status of antenatal, pre-marital and population screening of SCD and thalassaemia in countries with both high-and low prevalence of these conditions, methods of screening in use, and discusses some of the pitfalls, ethical issues and controversies surrounding antenatal screening. It also discusses outcomes of some screening programmes and recognises the need for the establishment of antenatal screening in areas where their prevalence is highest; namely sub-Saharan Africa and India.
Topics: Anemia, Sickle Cell; Female; Hemoglobinopathies; Humans; Pregnancy; Prenatal Diagnosis; Thalassemia
PubMed: 31509241
DOI: 10.1111/bjh.16188 -
Clinics (Sao Paulo, Brazil) 2022This work aimed to better understand the impact of pandemics of respiratory viruses on children with hemoglobinopathies through a comprehensive review of the literature.... (Review)
Review
This work aimed to better understand the impact of pandemics of respiratory viruses on children with hemoglobinopathies through a comprehensive review of the literature. MEDLINE, SCIELO, LILACS, and PUBMED were used as data sources to find articles without time period restrictions. Previous observations suggest that patients with hemoglobinopathies are a group especially susceptible to the complications of viral respiratory infections, with greater morbidity and mortality related to them. Within this context, this review found that, during the 2009 H1N1 pandemic, the risk of hospitalization in children and adults increased, especially in patients with a history of complications such as acute chest syndrome. In addition, the Coronavirus Disease 2019 (COVID-19) pandemic appears to have less repercussion among children with hemoglobinopathies compared to adults, similar to what is seen in the general population. In the H1N1 pandemic, patients with hemoglobinopathies behaved as a group more susceptible to complications, with increased morbidity and mortality. However, for COVID-19, the existing data to date on these patients do not show the same clinical impact. Thus, although these children deserve attention in case of infection due to their potential risks, they seem to have a favorable evolution.
Topics: Adult; COVID-19; Child; Hemoglobinopathies; Humans; Influenza A Virus, H1N1 Subtype; Pandemics; SARS-CoV-2
PubMed: 35113785
DOI: 10.1016/j.clinsp.2021.100004 -
American Journal of Obstetrics and... Jul 2022
Topics: COVID-19; Female; Hemoglobinopathies; Hemoglobins, Abnormal; Humans; Oxygen; Oxygen Saturation; Pregnancy
PubMed: 35218699
DOI: 10.1016/j.ajog.2022.02.027 -
International Journal of Molecular... Jun 2021Circulating hemopexin is the primary protein responsible for the clearance of heme; therefore, it is a systemic combatant against deleterious inflammation and oxidative... (Review)
Review
Circulating hemopexin is the primary protein responsible for the clearance of heme; therefore, it is a systemic combatant against deleterious inflammation and oxidative stress induced by the presence of free heme. This role of hemopexin is critical in hemolytic pathophysiology. In this review, we outline the current research regarding how the dynamic activity of hemopexin is implicated in sickle cell disease, which is characterized by a pathological aggregation of red blood cells and excessive hemolysis. This pathophysiology leads to symptoms such as acute kidney injury, vaso-occlusion, ischemic stroke, pain crises, and pulmonary hypertension exacerbated by the presence of free heme and hemoglobin. This review includes in vivo studies in mouse, rat, and guinea pig models of sickle cell disease, as well as studies in human samples. In summary, the current research indicates that hemopexin is likely protective against these symptoms and that rectifying depleted hemopexin in patients with sickle cell disease could improve or prevent the symptoms. The data compiled in this review suggest that further preclinical and clinical research should be conducted to uncover pathways of hemopexin in pathological states to evaluate its potential clinical function as both a biomarker and therapy for sickle cell disease and related hemoglobinopathies.
Topics: Anemia, Sickle Cell; Animals; Cytoprotection; Hemopexin; Humans; Immunomodulation; Lipoproteins; Microvessels
PubMed: 34203861
DOI: 10.3390/ijms22126408 -
Hematopoietic-Stem-Cell-Targeted Gene-Addition and Gene-Editing Strategies for β-hemoglobinopathies.Cell Stem Cell Feb 2021Sickle cell disease (SCD) is caused by a well-defined point mutation in the β-globin gene and therefore is an optimal target for hematopoietic stem cell (HSC)... (Review)
Review
Sickle cell disease (SCD) is caused by a well-defined point mutation in the β-globin gene and therefore is an optimal target for hematopoietic stem cell (HSC) gene-addition/editing therapy. In HSC gene-addition therapy, a therapeutic β-globin gene is integrated into patient HSCs via lentiviral transduction, resulting in long-term phenotypic correction. State-of-the-art gene-editing technology has made it possible to repair the β-globin mutation in patient HSCs or target genetic loci associated with reactivation of endogenous γ-globin expression. With both approaches showing signs of therapeutic efficacy in patients, we discuss current genetic treatments, challenges, and technical advances in this field.
Topics: CRISPR-Cas Systems; Gene Editing; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Hemoglobinopathies; Humans
PubMed: 33545079
DOI: 10.1016/j.stem.2021.01.001 -
Hematology/oncology Clinics of North... Apr 2016The inherited disorders of hemoglobin represent the most common monogenic diseases. This article provides a brief description of the main inherited disorders of... (Review)
Review
The inherited disorders of hemoglobin represent the most common monogenic diseases. This article provides a brief description of the main inherited disorders of hemoglobin and their classification, and summarizes progress made in the last decade toward a better awareness and recognition of these disorders as a global health problem. Also presented are the main demographic, genetic, and environmental factors that influence the present and future health burden of these disorders. The strengths and limitations of existing estimates and current health policies in high-, low-, and middle-income countries are discussed.
Topics: Cost of Illness; Developing Countries; Global Health; Hemoglobinopathies; Humans; Risk Factors
PubMed: 27040957
DOI: 10.1016/j.hoc.2015.11.004