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Seminars in Hematology Jan 2021Human hemoglobin switching describes the highly regulated, sequential expression of the 5 β-like globin genes (HBE, HBG2, HBG1, HBD and HBB) of the human β-globin gene... (Review)
Review
Human hemoglobin switching describes the highly regulated, sequential expression of the 5 β-like globin genes (HBE, HBG2, HBG1, HBD and HBB) of the human β-globin gene complex. The sequential activation of these β or β-like globin genes during human development from early embryonic through late fetal ('adult') stages, and during erythroid maturation, occurs in an order corresponding to their 5' to 3' location on chromosome 11. The β-hemoglobinopathies are the most common inherited diseases in humanity, and are diseases of mutated HBB or its altered regulation. Since the other β-like globin genes can potentially substitute for defective HBB, much translational research is directed toward understanding and manipulating sequential activation at the human β-globin gene complex to treat β-hemoglobinopathies. Non-human primates provide a vital contribution to such efforts because of their recapitulation of the developmental/maturational switch in hemoglobin production as observed in humans (mice do not model this switch). Valuable insights into druggable epigenetic forces that mediate the switch have been thereby gained. We review important lessons learned in non-human primates, complemented by other studies, and suggest rational next steps.
Topics: Animals; Epigenesis, Genetic; Hemoglobinopathies; Humans; Mice; Primates; beta-Globins
PubMed: 33509438
DOI: 10.1053/j.seminhematol.2020.12.001 -
Expert Review of Hematology Oct 2021Drug efficacy and toxicity are closely related to the unique genetic profile of individuals, or pharmacogenomics. Despite the fact that cardiology, psychiatry and...
Drug efficacy and toxicity are closely related to the unique genetic profile of individuals, or pharmacogenomics. Despite the fact that cardiology, psychiatry and oncology are among the clinical specialties in which pharmacogenomics has become a clinical reality, the utility of pharmacogenomics has yet to be demonstrated for several other medical specialties. Over the last 15 years, genomic variants in a number of loci have been shown to be significantly associated with the fetal hemoglobin (HbF) response to hydroxyurea, the only approved drug for HbF induction for sickle cell disease. Here, we provide an update and discuss future challenges to the application of pharmacogenomics to improve therapies for β-hemoglobinopathies in relation to the current pharmacological treatment modalities for those disorders.
Topics: Anemia, Sickle Cell; Hemoglobinopathies; Humans; Hydroxyurea; Pharmacogenetics; beta-Thalassemia
PubMed: 34490838
DOI: 10.1080/17474086.2021.1977117 -
JPMA. the Journal of the Pakistan... Jan 2021Beta thalassemia in Pakistan is a serious health concern with an estimated 5-8% carrier frequency and birth of 5000 major children every year in the country. The... (Review)
Review
Beta thalassemia in Pakistan is a serious health concern with an estimated 5-8% carrier frequency and birth of 5000 major children every year in the country. The treatment of beta thalassemia major patients poses a great economic burden; hence, the ideal approach towards this disease should encompass effective prevention services. At present only one government funded project "Punjab Thalassemia Prevention Programme" existed in Punjab province, and providing free of cost services for beta thalassemia screening and prenatal diagnosis. Complete blood count and haemoglobin electrophoresis remains the preliminary test for screening, while chorionic villi sampling and amplification refractory mutation system method have been most widely used for molecular diagnosis of beta thalassemia. Modern molecular techniques, non-invasive prenatal diagnosis, and pre-implantation diagnosis are in trial phases. In this review we have discussed the available diagnostic facilities and status of prevention programmes for beta thalassemia in Pakistan as well as future perspectives.
Topics: Child; Chorionic Villi Sampling; Female; Humans; Pakistan; Pregnancy; Prenatal Diagnosis; Thalassemia; beta-Thalassemia
PubMed: 35157672
DOI: 10.47391/JPMA.665 -
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 -
Best Practice & Research. Clinical... Sep 2022Throughout the Coronavirus Disease 2019 (COVID-19) pandemic, understanding the effects of COVID-19 on persons with Sickle Cell Disease (SCD) and Sickle Cell Trait (SCT)... (Review)
Review
Throughout the Coronavirus Disease 2019 (COVID-19) pandemic, understanding the effects of COVID-19 on persons with Sickle Cell Disease (SCD) and Sickle Cell Trait (SCT) has garnered interest. Patients with SCD diagnosed with COVID-19 utilize the emergency department and are hospitalized at significantly higher rates compared to the general population, with vaso-occlusive crisis and acute chest syndrome as the leading presentations. Whether SCD alone increases the likelihood of severe COVID-19 illness remains uncertain; however, potential risk factors for severe disease among patients with SCD include older age, frequent acute care visits for pain, haemoglobin SC disease, and pre-existing end-organ disease. SCT status may also influence COVID-19 outcomes, particularly among those with pre-existing co-morbidities. Corticosteroids in patients with SCD and COVID-19 should be used with extreme caution given strong associations between corticosteroid exposure and severe vaso-occlusive crisis, with prophylactic transfusion administered if corticosteroids are deemed necessary. Hydroxyurea may be protective in COVID-19.
Topics: Humans; Sickle Cell Trait; COVID-19; Anemia, Sickle Cell; Hydroxyurea; Risk Factors
PubMed: 36494153
DOI: 10.1016/j.beha.2022.101382 -
Biosensors Apr 2023Thalassemia is a monogenic autosomal recessive disorder caused by mutations, which lead to abnormal or reduced production of hemoglobin. Ineffective erythropoiesis,... (Review)
Review
Thalassemia is a monogenic autosomal recessive disorder caused by mutations, which lead to abnormal or reduced production of hemoglobin. Ineffective erythropoiesis, hemolysis, hepcidin suppression, and iron overload are common manifestations that vary according to genotypes and dictate, which diagnosis and therapeutic modalities, including transfusion therapy, iron chelation therapy, HbF induction, gene therapy, and editing, are performed. These conventional therapeutic methods have proven to be effective, yet have several disadvantages, specifically iron toxicity, associated with them; therefore, there are demands for advanced therapeutic methods. Nanotechnology-based applications, such as the use of nanoparticles and nanomedicines for theragnostic purposes have emerged that are simple, convenient, and cost-effective methods. The therapeutic potential of various nanoparticles has been explored by developing artificial hemoglobin, nano-based iron chelating agents, and nanocarriers for globin gene editing by CRISPR/Cas9. Au, Ag, carbon, graphene, silicon, porous nanoparticles, dendrimers, hydrogels, quantum dots, etc., have been used in electrochemical biosensors development for diagnosis of thalassemia, quantification of hemoglobin in these patients, and analysis of conventional iron chelating agents. This review summarizes the potential of nanotechnology in the development of various theragnostic approaches to determine thalassemia-causing gene mutations using various nano-based biosensors along with the employment of efficacious nano-based therapeutic procedures, in contrast to conventional therapies.
Topics: Humans; Erythropoiesis; Thalassemia; Iron Chelating Agents; Hemoglobins; Iron
PubMed: 37185525
DOI: 10.3390/bios13040450 -
Archives of Gynecology and Obstetrics Nov 2021To determine the risk of adverse maternal and neonatal outcomes in pregnant women with a hemoglobinopathy trait.
PURPOSE
To determine the risk of adverse maternal and neonatal outcomes in pregnant women with a hemoglobinopathy trait.
MATERIALS AND METHODS
Retrospective cohort study was conducted to compare adverse maternal and neonatal outcomes between pregnant women with a hemoglobinopathy trait (study group; n = 172), and without a hemoglobinopathy trait (control group; n = 360). The medical data were extracted from clinical records of pregnant women attending antenatal care and delivering at the University Hospital Basel or University Hospital Zurich between 2015 and 2018.
RESULTS
A total of 172 pregnant women with a hemoglobinopathy trait and 360 controls were recruited. Apart from fetal acidosis, the groups did not differ significantly in any variables of adverse neonatal outcomes. Whereas, among the maternal outcomes the rate of abortion, gestational diabetes mellitus, bacteriuria or urinary tract infection, intrahepatic cholestasis, abnormal placentation and anemia postpartum were significantly increased in women with a hemoglobinopathy trait.
CONCLUSION
In our study, a hemoglobinopathy trait increased the risk of adverse maternal outcomes but did not increase adverse neonatal outcomes.
Topics: Acidosis; Adolescent; Adult; Bacteriuria; Case-Control Studies; Female; Hemoglobinopathies; Humans; Infant, Newborn; Middle Aged; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy Outcome; Retrospective Studies; Young Adult
PubMed: 33842991
DOI: 10.1007/s00404-021-06058-y -
Orphanet Journal of Rare Diseases May 2024Brain injury in hereditary hemoglobinopathies is commonly attributed to anemia-related relative hypoperfusion in terms of impaired oxygen blood supply. Supratentorial...
BACKGROUND
Brain injury in hereditary hemoglobinopathies is commonly attributed to anemia-related relative hypoperfusion in terms of impaired oxygen blood supply. Supratentorial and infratentorial vascular watershed regions seem to be especially vulnerable, but data are very scarce.
AIMS
We investigated a large beta-thalassemia sample with arterial spin labeling in order to characterize regional perfusion changes and their correlation with phenotype and anemia severity.
METHODS
We performed a multicenter single-scanner cross-sectional 3T-MRI study analyzing non-invasively the brain perfusion in 54 transfusion-dependent thalassemia (TDT), 23 non-transfusion-dependent thalassemia (NTDT) patients and 56 Healthy Controls (HC). Age, hemoglobin levels, and cognitive functioning were recorded.
RESULTS
Both TDT and NTDT patients showed globally increased brain perfusion values compared to healthy controls, while no difference was found between patient subgroups. Using age and sex as covariates and scaling the perfusion maps for the global cerebral blood flow, beta-thalassemia patients showed relative hyperperfusion in supratentorial/infratentorial watershed regions. Perfusion changes correlated with hemoglobin levels (p = 0.013) and were not observed in the less severely anemic patients (hemoglobin level > 9.5 g/dL). In the hyperperfused regions, white matter density was significantly decreased (p = 0.0003) in both patient subgroups vs. HC. In NTDT, white matter density changes correlated inversely with full-scale Intelligence Quotient (p = 0.007) while in TDT no correlation was found.
CONCLUSION
Relative hyperperfusion of watershed territories represents a hemodynamic hallmark of beta-thalassemia anemia challenging previous hypotheses of brain injury in hereditary anemias. A careful management of anemia severity might be crucial for preventing structural white matter changes and subsequent long-term cognitive impairment.
Topics: Humans; beta-Thalassemia; Male; Female; Adult; Magnetic Resonance Imaging; Cross-Sectional Studies; Brain; Young Adult; Cerebrovascular Circulation; Adolescent; Middle Aged; Child
PubMed: 38773534
DOI: 10.1186/s13023-024-03194-x -
Blood Oct 2019β-Thalassemia and sickle cell disease (SCD) are the most prevalent monogenic diseases. These disorders are caused by quantitative or qualitative defects in the... (Review)
Review
β-Thalassemia and sickle cell disease (SCD) are the most prevalent monogenic diseases. These disorders are caused by quantitative or qualitative defects in the production of adult hemoglobin. Gene therapy is a potential treatment option for patients lacking an allogenic compatible hematopoietic stem cell (HSC) donor. New-generation lentiviral vectors (LVs) carrying a β-globin-like gene have revolutionized this field by allowing effective HSC transduction, with no evidence of genotoxicity to date. Several clinical trials with different types of vector are underway worldwide; the initial results are encouraging with regard to the sustained production of therapeutic hemoglobin, improved biological parameters, a lower transfusion requirement, and better quality of life. Long-term follow-up studies will confirm the safety of LV-based gene therapy. The optimization of patient conditioning, HSC harvesting, and HSC transduction has further improved the therapeutic potential of this approach. Novel LV-based strategies for reactivating endogenous fetal hemoglobin (HbF) are also promising, because elevated HbF levels can reduce the severity of both β-thalassemia and SCD. Lastly, genome-editing approaches designed to correct the disease-causing mutation or reactivate HbF are currently under investigation. Here, we discuss the clinical outcomes of current LV-based gene addition trials and the promising advantages of novel alternative therapeutic strategies.
Topics: Anemia, Sickle Cell; Animals; Clinical Trials as Topic; Fetal Hemoglobin; Gene Editing; Genetic Therapy; Genetic Vectors; Hemoglobinopathies; Humans; Lentivirus; beta-Globins; beta-Thalassemia
PubMed: 31467062
DOI: 10.1182/blood.2019000949 -
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