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Indian Pediatrics Jul 2021b-Thalassemia is one of the most prevalent monogenic diseases usually caused by quantitative defects in the production of b-globin, a component of adult hemoglobin...
b-Thalassemia is one of the most prevalent monogenic diseases usually caused by quantitative defects in the production of b-globin, a component of adult hemoglobin (a2b2), leading to severe anemia. Technological advances in genome sequencing, stem cell selection, viral vector development, transduction and gene-editing strategies now allow for efficient ex-vivo genetic manipulation of human hematopoietic stem cells that can lead to a meaningful clinical benefit in thalassemia patients. In this perspective, the status of the gene-therapy approaches available for transfusion-dependent thalassemia and early results of clinical trials are discussed. It is highly anticipated that gene therapies will soon become a treatment option for patients lacking compatible donors for hematopoietic stem cell transplant and will offer a suitable alternative for definitive treatment of b-thalassemia, even in young children.
Topics: Child, Preschool; Genetic Therapy; Genetic Vectors; Hemoglobins; Humans; Thalassemia; beta-Thalassemia
PubMed: 33772535
DOI: No ID Found -
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 -
Journal of the Neurological Sciences Nov 2022Sickle cell disease (SCD) is an inherited hemoglobinopathy affecting approximately 100,000 individuals in the United States. Cerebrovascular disease is among the most... (Review)
Review
Sickle cell disease (SCD) is an inherited hemoglobinopathy affecting approximately 100,000 individuals in the United States. Cerebrovascular disease is among the most common and debilitating complications of SCA, with 53% experiencing silent cerebral infarct by age 30 and 3.8% experiencing overt stroke by age 40 years. This review highlights the burden of cerebrovascular disease in SCD, including both stroke and silent cerebral infarct (SCI). We then discuss the pathophysiology of stroke and cerebral fat embolism in the absence of a patent foramen ovale. This review also reveals that options for primary and secondary stroke prevention in SCD are still limited to hydroxyurea and blood transfusion, and that the role of aspirin and anticoagulation in SCD stroke has not been adequately studied. Limited data suggest that the novel disease-modifying agents for SCD management may improve renal dysfunction, leg ulcers, and lower the abnormally high TCD flow velocity. Further research is urgently needed to investigate their role in stroke prevention in SCD, as these novel agents target the main stroke contributors in SCD - hemolysis and vaso-occlusion. This literature review also explores the role of healthcare disparities in slowing progress in SCD management and research in the United States, highlighting the need for more investment in patient and clinician education, SCD management, and research.
Topics: Humans; Adult; Hydroxyurea; Anemia, Sickle Cell; Stroke; Cerebral Infarction; Aspirin; Anticoagulants; Ultrasonography, Doppler, Transcranial
PubMed: 36150233
DOI: 10.1016/j.jns.2022.120412 -
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 -
Frontiers in Immunology 2020Allogeneic hematopoietic cell transplant (HCT) is curative for pediatric patients with non-malignant hematopoietic disorders, including hemoglobinopathies, bone marrow... (Review)
Review
Allogeneic hematopoietic cell transplant (HCT) is curative for pediatric patients with non-malignant hematopoietic disorders, including hemoglobinopathies, bone marrow failure syndromes, and primary immunodeficiencies. Early establishment of donor-derived innate and adaptive immunity following HCT is associated with improved overall survival, lower risk of infections and decreased incidence of graft failure. Immune reconstitution (IR) is impacted by numerous clinical variables including primary disease, donor characteristics, conditioning regimen, and graft versus host disease (GVHD). Recent advancements in HCT have been directed at reducing toxicity of conditioning therapy, expanding donor availability through use of alternative donor sources, and addressing morbidity from GVHD with novel graft manipulation. These novel transplant approaches impact the kinetics of immune recovery, which influence post-transplant outcomes. Here we review immune reconstitution in pediatric patients undergoing HCT for non-malignant disorders. We explore the transplant-associated factors that influence immunologic recovery and the disease-specific associations between IR and transplant outcomes.
Topics: Age Factors; Child; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Hemoglobinopathies; Humans; Immune Reconstitution; Primary Immunodeficiency Diseases; Risk Factors; Tissue Donors; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome
PubMed: 33013851
DOI: 10.3389/fimmu.2020.01988 -
Biosensors Feb 2024Hemoglobin (Hb) disorders are among the most common monogenic diseases affecting nearly 7% of the world population. Among various Hb disorders, approximately 1.5% of the...
Hemoglobin (Hb) disorders are among the most common monogenic diseases affecting nearly 7% of the world population. Among various Hb disorders, approximately 1.5% of the world population carries -thalassemia (-Thal), affecting 40,000 newborns every year. Early screening and a timely diagnosis are essential for -thalassemia patients for the prevention and management of later clinical complications. However, in Africa, Southern Europe, the Middle East, and Southeast Asia, where -thalassemia is most prevalent, the diagnosis and screening for -thalassemia are still challenging due to the cost and logistical burden of laboratory diagnostic tests. Here, we present Gazelle, which is a paper-based microchip electrophoresis platform that enables the first point-of-care diagnostic test for -thalassemia. We evaluated the accuracy of Gazelle for the -Thal screening across 372 subjects in the age range of 4-63 years at Apple Diagnostics lab in Mumbai, India. Additionally, 30 blood samples were prepared to mimic -Thal intermediate and -Thal major samples. Gazelle-detected levels of Hb A, Hb F, and Hb A demonstrated high levels of correlation with the results reported through laboratory gold standard high-performance liquid chromatography (HPLC), yielding a Pearson correlation coefficient = 0.99. This ability to obtain rapid and accurate results suggests that Gazelle may be suitable for the large-scale screening and diagnosis of -Thal.
Topics: Infant, Newborn; Humans; Animals; Child, Preschool; Child; Adolescent; Young Adult; Adult; Middle Aged; beta-Thalassemia; Antelopes; Hemoglobinopathies; Chromatography, High Pressure Liquid
PubMed: 38392002
DOI: 10.3390/bios14020083 -
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 -
Blood Jan 2023
Topics: Humans; Anemia, Sickle Cell; Hemoglobinopathies; Glycolipids
PubMed: 36633883
DOI: 10.1182/blood.2022018075 -
Frontiers in Bioscience (Landmark... Mar 2020Stem cells exist in many niches throughout the body and have the ability to self replicate and to differentiate to many lineages. As of a result of the advances in stem... (Review)
Review
Stem cells exist in many niches throughout the body and have the ability to self replicate and to differentiate to many lineages. As of a result of the advances in stem cell-based therapies, regenerative medicine is witnessing remarkable development. Encouraging positive outcomes from the use of stem cells in various diseases are extremely promising.. The popularity of stem cell-based therapy is due to its flexibility and potent approach in the treatment of numerous diseases. Treatment with genetically configured HSCs favors the engraftment of transplantation without rejection. MSCs hold an immunoregulatory capacity, elicit immunosuppressive effects and are immune-privileged cells, due to the low expression of MHCII and costimulatory molecules on their cell surface. Encouraging, positive outcomes from the use of stem cells in immunodeficiency, cancer, hemoglobinopathy, bone, cartilage repair, autoimmune disorders, cardiac and neuronal diseases are extremely promising. Successful stem cells based clinical trials are the game changers in the progress of clinical use of stem cells. This review provides an up to date comprehensive overview of the clinical efficacy of stem cells.
Topics: Genetic Engineering; Genetic Therapy; Humans; Leukemia; Lymphoma; Neoplasms; Stem Cell Transplantation; Stem Cells; Transplantation, Homologous; beta-Thalassemia
PubMed: 32114445
DOI: 10.2741/4868 -
Journal of Thrombosis and Thrombolysis Oct 2021Sickle cell disease (SCD) is an inherited monogenic hemoglobinopathy characterized by formation of sickle erythrocytes under conditions of deoxygenation. Sickle... (Review)
Review
Sickle cell disease (SCD) is an inherited monogenic hemoglobinopathy characterized by formation of sickle erythrocytes under conditions of deoxygenation. Sickle erythrocytes can lead to thrombus formation and vaso-occlusive episodes that may result in hemolytic anemia, pain crisis and multiple organ damage. Moreover, SCD is characterized by endothelial damage, increased inflammatory response, platelet activation and aggravation, and activation of both the intrinsic and the extrinsic coagulation pathways. Cerebrovascular events constitute an important clinical complication of SCD. Children with SCD have a 300-fold higher risk of acute stroke and by the age of 45 about 25% of patients have suffered an overt stoke. Management and prevention of stroke in patients with SCD is not well defined. Moreover, the presence of patent foramen ovale (PFO) increases the risk of the occurrence of an embolic cerebrovascular event. The role of PFO closure and antiplatelet or anticoagulation therapy has not been well investigated. Moreover, during COVID-19 pandemic and taking into account the increased rates of thrombotic events and the difficulties in blood transfusion, management of SCD patients is even more challenging and difficult, since data are scarce regarding stroke occurrence and management in this specific population in the COVID-19 era. This review focuses on pathophysiology of stroke in patients with SCD and possible treatment strategies in the presence of PFO.
Topics: Anemia, Sickle Cell; COVID-19; Foramen Ovale, Patent; Humans; Primary Prevention; Prognosis; Recurrence; Risk Assessment; Risk Factors; Secondary Prevention; Stroke
PubMed: 33638018
DOI: 10.1007/s11239-021-02398-3