bims-conane 2024-10-06 papers

bims-conane

Biomed News

on Congenital anemias

Issue of 2024‒10‒06
thirteen papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo

Vamifeport: Monography of the First Oral Ferroportin Inhibitor.
Erythropoiesis: insights from a genomic perspective.
Potential Use of MicroRNA Technology in Thalassemia Therapy.
Glucose-6-phosphate dehydrogenase deficiency detection using fluorocytometric assay: Evaluation after 1 year of clinical implementation.
Application of third-generation sequencing technology for identifying rare α- and β-globin gene variants in a Southeast Chinese region.
Modulation of Antioxidant Enzyme Expression of In Vitro Culture-Derived Reticulocytes.
Adverse clinical outcomes associated with sickle cell trait at high altitude.
The Effect of Globalization on Hemoglobinopathies and its Genetic Inheritance: The Booster Effect of Genetic Combinations.
[Pathophysiology of sideroblastic anemia].
Evaluation of Glucose 6-Phosphate Dehydrogenase, Pyruvate Kinase, and New Generation Inflammation Biomarkers in Prolonged Neonatal Jaundice.
A rare glimpse of Fessas bodies in a patient with β-thalassemia major postsplenectomy.
Integrated metabolomic and microbiome analysis identifies Cupriavidus metallidurans as a potential therapeutic target for β-thalassemia.
Deciphering Transcriptomic Variations in Hematopoietic Lineages: HSCs, EBs, and MKs.

J Clin Med. 2024 Sep 18. pii: 5524. [Epub ahead of print]13(18):

Vamifeport: Monography of the First Oral Ferroportin Inhibitor.

Federica Pilo, Emanuele Angelucci.

  Over the last few years, several mechanisms that are involved in congenital diseases characterized by ineffective erythropoiesis have been described. Therefore, multiple new target drugs are being developed in preclinical models against the main regulators of normal erythropoiesis. Above all, the key mechanism that regulates systemic iron homeostasis, represented by the hepcidin-ferroportin axis, is considered to be the target for new therapies. The main hypothesis is that iron restriction, through blocking ferroportin (the unique iron transporter in mammals) in such diseases, ameliorates erythropoiesis. The action of vamifeport is different from the currently approved drugs in this setting since it acts straight on the ferroportin-hepcidin axis. The data presented in the sickle cell disease (SCD) Townes mouse model showed a preclinical proof-of-concept for the efficacy of oral ferroportin inhibitor. Vamifeport reduced hemoglobin concentration in red blood cells (RBCs) and diminished intravascular hemolysis and inflammation, improving hemodynamics and preventing vascular occlusive crises. On this basis, clinical trials were commenced in patients with SCD, non-transfusion-dependent (NTD) thalassemia and transfusion-dependent (TD) thalassemia. Preliminary data in NTD thalassemic patients also confirm the safety and efficacy in decreasing iron level. In conclusion, vamifeport represents a new option in the panorama of drugs targeting the hepcidin-ferroportin axis, but its efficacy is still under investigation as a single agent.

Keywords:  ferroportin; hepcidin; sickle cell disease; thalassemia

DOI:  https://doi.org/10.3390/jcm13185524
Exp Mol Med. 2024 Oct 01.

Erythropoiesis: insights from a genomic perspective.

Hye Ji Cha.

Erythropoiesis, the process underlying the production of red blood cells, which are essential for oxygen transport, involves the development of hematopoietic stem cells into mature red blood cells. This review focuses on the critical roles of transcription factors and epigenetic mechanisms in modulating gene expression critical for erythroid differentiation. It emphasizes the significance of chromatin remodeling in ensuring gene accessibility, a key factor for the orderly progression of erythropoiesis. This review also discusses how dysregulation of these processes can lead to erythroid disorders and examines the promise of genome editing and gene therapy as innovative therapeutic approaches. By shedding light on the genomic regulation of erythropoiesis, this review suggests avenues for novel treatments for hematological conditions, underscoring the need for continued molecular studies to improve human health.

DOI: https://doi.org/10.1038/s12276-024-01311-1
J Clin Med Res. 2024 Sep;16(9): 411-422

Potential Use of MicroRNA Technology in Thalassemia Therapy.

Lantip Rujito, Tirta Wardana, Wahyu Siswandari, Ita Margaretha Nainggolan, Teguh Haryo Sasongko.

  Thalassemia encompasses a group of inherited hemoglobin disorders characterized by reduced or absent production of the α- or β-globin chains, leading to anemia and other complications. Current management relies on lifelong blood transfusions and iron chelation, which is burdensome for patients. This review summarizes the emerging therapeutic potential of modulating microRNAs (miRNAs) to treat thalassemia. MiRNAs are small non-coding RNAs that regulate gene expression through sequence-specific binding to messenger RNAs (mRNAs). While they commonly repress gene expression by binding to the 3' untranslated regions (UTRs) of target mRNAs, miRNAs can also interact with 5'UTRs and gene promoters to activate gene expression. Many miRNAs are now recognized as critical regulators of erythropoiesis and are abnormally expressed in β-thalassemia. Therapeutically restoring levels of deficient miRNAs or inhibiting overexpression through miRNA mimics or inhibitors (antagomir), respectively, has shown preclinical efficacy in ameliorating thalassemic phenotypes. The miR-144/451 cluster is especially compelling for targeted upregulation to reactivate fetal hemoglobin synthesis. Advances in delivery systems are addressing previous challenges in stability and targeting of miRNA-based drugs. While still early, gene therapy studies suggest combinatorial approaches with miRNA modulation may provide synergistic benefits. Several key considerations remain including enhancing delivery, minimizing off-target effects, and demonstrating long-term safety and efficacy. While no miRNA therapies have yet progressed to clinical testing for thalassemia specifically, important lessons are being learned through clinical trials for other diseases and conditions, such as cancer, cardiovascular diseases, and viral. If limitations can be overcome through multi-disciplinary collaboration, miRNAs hold great promise to expand and transform treatment options for thalassemia in the future by precisely targeting pathogenic molecular networks. Ongoing innovations, such as advancements in miRNA delivery systems, improved targeting mechanisms, and enhanced understanding of miRNA biology, continue to drive progress in this emerging field towards realizing the clinical potential of miRNA-based medicines for thalassemia patients.

Keywords:  Erythropoiesis; MiRNA; MiRNA-based therapy; Thalassemia; Transfusion therapy

DOI:  https://doi.org/10.14740/jocmr5245
Cytometry B Clin Cytom. 2024 Oct 02.

Glucose-6-phosphate dehydrogenase deficiency detection using fluorocytometric assay: Evaluation after 1 year of clinical implementation.

M Souissi, E Bera, C Boutet, C Chatellier, C Conte, E Brard, C Boquet, E Rousseau, S Pissard, A Lahary, V Bobée.

  Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common enzymopathy that affects red blood cells (RBCs) and renders them susceptible to oxidative stress. G6PD deficiency can cause hemolytic anemia, especially after exposure to certain drugs or infections. The diagnosis of G6PD deficiency is usually based on spectrophotometric measurement of enzyme activity, but this method has limitations in heterozygous females and in patients with other hematological disorders. In this study, we evaluated the use of flow cytometry as an alternative method for detecting G6PD deficiency in 514 samples (265 females and 249 males) from a clinical laboratory. We compared the results of flow cytometry with those of spectrophotometry and molecular analysis, and assessed the performance of flow cytometry in different subgroups of patients. We found that flow cytometry was able to identify G6PD deficiency in most cases, with high sensitivity and specificity. Flow cytometry also allowed the quantification of the percentage of G6PD-deficient RBCs, which varied among heterozygous females due to X-chromosome inactivation. Moreover, flow cytometry detected several cases of G6PD deficiency that were missed by spectrophotometry, especially in heterozygous females with normal or subnormal enzyme activity. However, flow cytometry also showed some false negative results, mainly in patients with sickle cell disease. Therefore, flow cytometry is a reliable and efficient tool for screening G6PD deficiency, but some precautions should be taken in interpreting the results in patients with other hematological conditions.

Keywords:  G6PD deficiency; clinical hematology; diagnostic test; flow cytometry

DOI:  https://doi.org/10.1002/cyto.b.22207
BMC Med Genomics. 2024 Oct 01. 17(1): 241

Application of third-generation sequencing technology for identifying rare α- and β-globin gene variants in a Southeast Chinese region.

Jianlong Zhuang, Junyu Wang, Nan Huang, Yu Zheng, Liangpu Xu.

  BACKGROUND: Third-generation sequencing (TGS) based on long-read technology has been gradually used in identifying thalassemia and hemoglobin (Hb) variants. The aim of the present study was to explore genotype varieties of thalassemia and Hb variants in Quanzhou region of Southeast China by TGS.METHODS: Included in this study were 6,174 subjects with thalassemia traits from Quanzhou region of Southeast China. All of them underwent common thalassemia gene testing using the DNA reverse dot-blot hybridization technology. Subjects who were suspected as rare thalassemia carriers were further subjected to TGS to identify rare or novel α- and β-globin gene variants, and the results were verified by Sanger sequencing and/or gap PCR.
RESULTS: Of the 6,174 included subjects, 2,390 (38.71%) were identified as α- and β-globin gene mutation carriers, including 40 carrying rare or novel α- and β-thalassemia mutations. The αCD30(-GAG)α and Hb Lepore-Boston-Washington were first reported in Fujian province Southeast China. Moreover, the βCD15(TGG> TAG), βIVS-II-761, β0-Filipino(~ 45 kb deletion), and Hb Lepore-Quanzhou were first identified in the Chinese population. In addition, 35 cases of Hb variants were detected, the rare Hb variants of Hb Jilin and Hb Beijing were first reported in Fujian province of China. Among them, one case with compound αααanti3.7 and Hb G-Honolulu variants was identified in this study.
CONCLUSION: Our findings may provide valuable data for enriching the spectrum of thalassemia and highlight the clinical application value of TGS-based α- and β-globin genetic testing.

Keywords:  Hb variants; Sanger sequencing; Thalassemia; Third-generation sequencing

DOI:  https://doi.org/10.1186/s12920-024-02014-2
Antioxidants (Basel). 2024 Sep 02. pii: 1070. [Epub ahead of print]13(9):

Modulation of Antioxidant Enzyme Expression of In Vitro Culture-Derived Reticulocytes.

Hannah D Langlands, Deborah K Shoemark, Ashley M Toye.

  The regulation of reactive oxygen species (ROS) in red blood cells (RBCs) is crucial for maintaining functionality and lifespan. Indeed, dysregulated ROS occurs in haematological diseases such as sickle cell disease and β-thalassaemia. In order to combat this, RBCs possess high levels of protective antioxidant enzymes. We aimed to further boost RBC antioxidant capacity by overexpressing peroxiredoxin (Prxs) and glutathione peroxidase (GPxs) enzymes. Multiple antioxidant enzyme cDNAs were individually overexpressed in expanding immortalised erythroblasts using lentivirus, including Prx isoforms 1, 2, and 6 and GPx isoforms 1 and 4. Enhancing Prx protein expression proved straightforward, but GPx overexpression required modifications. For GPx4, these modifications included adding a SECIS element in the 3'UTR, the removal of a mitochondrial-targeting sequence, and removing putative ubiquitination sites. Culture-derived reticulocytes exhibiting enhanced levels of Prx and GPx antioxidant proteins were successfully engineered, demonstrating a novel approach to improve RBC resilience to oxidative stress. Further work is needed to explore the activity of these proteins and their impact on RBC metabolism, but this strategy shows promise for improving RBC function in physiological and pathological contexts and during storage for transfusion. Enhancing the antioxidant capacity of reticulocytes has exciting promise for developing culture-derived RBCs with enhanced resistance to oxidative damage and offers new therapeutic interventions in diseases with elevated oxidative stress.

Keywords:  antioxidant enzyme; erythroid; glutathione peroxidase; peroxiredoxin; reactive oxygen species

DOI:  https://doi.org/10.3390/antiox13091070
Haematologica. 2024 Oct 03.

Adverse clinical outcomes associated with sickle cell trait at high altitude.

Katherine A Stafford, Soravis Osataphan, Rushad Patell, Nigel S Key.

Not available.

DOI: https://doi.org/10.3324/haematol.2024.285832
Acta Med Port. 2024 Oct 01. 37(10): 746-747

The Effect of Globalization on Hemoglobinopathies and its Genetic Inheritance: The Booster Effect of Genetic Combinations.

Catarina Guerreiro Ferreira, Ana Filipa Lima, Adelina Sitari, Anabela Ferrão, Elsa Rocha.



Keywords:  Hemoglobinopathies/epidemiology; Transients and Migrants; beta-Thalassemia

DOI:  https://doi.org/10.20344/amp.21772
Rinsho Ketsueki. 2024 ;65(9): 911-919

[Pathophysiology of sideroblastic anemia].

Tohru Fujiwara.

  Sideroblastic anemias (SAs) are a diverse group of congenital and acquired disorders, characterized by anemia and the presence of ring sideroblasts in bone marrow. Congenital SA is a rare disorder that results from genetic mutations that impair heme biosynthesis, iron-sulfur [Fe-S] cluster biosynthesis, and mitochondrial protein synthesis. The predominant type of congenital SA is X-linked sideroblastic anemia, caused by mutations in the erythroid-specific δ-aminolevulinate synthase (ALAS2) gene, a key enzyme in the heme biosynthesis pathway in erythroid cells. SAs can also arise due to exposure to certain drugs or alcohol or to copper deficiency (secondary SAs). They are also often associated with myelodysplastic syndrome (idiopathic SA), and idiopathic SAs are the most frequently encountered type. This review discusses the current understanding of the pathophysiology underlying SA.

Keywords:  Gene mutation; Heme; Ring sideroblast; Sideroblastic anemia

DOI:  https://doi.org/10.11406/rinketsu.65.911
Medicina (Kaunas). 2024 Sep 12. pii: 1491. [Epub ahead of print]60(9):

Evaluation of Glucose 6-Phosphate Dehydrogenase, Pyruvate Kinase, and New Generation Inflammation Biomarkers in Prolonged Neonatal Jaundice.

Omer Okuyan, Seyma Dumur, Neval Elgormus, Hafize Uzun.

  Background and Objectives: To evaluate the clinical findings of glucose 6-phosphate dehydrogenase (G6PD) and pyruvate kinase (PK) deficiency in prolonged jaundice and to determine whether the systemic immune inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) can be used in the diagnosis of neonatal prolonged jaundice. Materials and Methods: Among full-term neonates with hyperbilirubinemia who were admitted to Medicine Hospital between January 2019 and January 2024 with the complaint of jaundice, 167 infants with a serum bilirubin level above 10 mg/dL, whose jaundice persisted after the 10th day, were included in this study. Results: G6PD activity was negatively correlated with NLR, SII, age, and hematocrit (Hct). There was a weak negative correlation between G6PD and NLR and a moderate negative correlation between G6PD activity and SII when adjusted for age and Hct. PK activity showed no significant correlation with G6PD, NLR, PLR, SII, age, and Hct. A linear relationship was observed between G6PD activity and SII and NLR. Conclusions: NLR and SII can be easily calculated in the evaluation of prolonged jaundice in G6PD deficiency has a considerable advantage. NLR and SII levels may contribute by preventing further tests for prolonged jaundice and regulating its treatment. It may be useful to form an opinion in emergencies and in early diagnostic period.

Keywords:  breast milk; glucose 6-phosphate dehydrogenase; neutrophil-to-lymphocyte ratio; prolonged jaundice; pyruvate kinase; systemic immune inflammation index

DOI:  https://doi.org/10.3390/medicina60091491
Blood. 2024 Oct 03. 144(14): 1543

A rare glimpse of Fessas bodies in a patient with β-thalassemia major postsplenectomy.

Kevin Shopsowitz, Habib Moshref Razavi.

DOI: https://doi.org/10.1182/blood.2024025262
Ann Hematol. 2024 Oct 01.

Integrated metabolomic and microbiome analysis identifies Cupriavidus metallidurans as a potential therapeutic target for β-thalassemia.

Xianfeng Guo, Sheng Lin, Xuchao Zhang, Min Li, Zi Wang, Yuanliang Peng, Xiaofeng He, Jing Liu.

  β-thalassemia(β-TH) is an inherited hemoglobin disorder marked by ineffective erythropoiesis, anemia, splenomegaly, and systemic iron overload, predominantly affecting developing countries in tropical and subtropical regions. Despite extensive research on its pathogenesis, the interactions between gut microbiota and metabolites in β-TH remain poorly understood. This study compares fecal metabolomics and metagenomics between wildtype (Wt) and heterozygous Th3/+ mice, a model for non-transfusion-dependent β-thalassemia intermedia. Our results show increased intestinal bilirubin metabolism, with significant elevations in metabolites such as biliverdin, bilirubin, and stercobilin. Metagenomic analysis revealed notable differences in bacterial composition between Th3/+ and Wt mice. Specifically, Cupriavidus metallidurans was identified as a key bacterium that mitigates anemia by reducing liver and spleen iron deposition. This is the first study to ameliorate anemia in mice by altering gut microbiota, presenting new strategies for β-TH management.

Keywords:  Anemia; Cupriavidus metallidurans; Metabolomics; Metagenome; Β-thalassemia

DOI:  https://doi.org/10.1007/s00277-024-06016-z
Int J Mol Sci. 2024 Sep 19. pii: 10073. [Epub ahead of print]25(18):

Deciphering Transcriptomic Variations in Hematopoietic Lineages: HSCs, EBs, and MKs.

Swati Dahariya, Anton Enright, Santosh Kumar, Ravi Kumar Gutti.

  In the realm of hematopoiesis, hematopoietic stem cells (HSCs) serve as pivotal entities responsible for generating various blood cell types, initiating both the myeloid and lymphoid branches within the hematopoietic lineage. This intricate process is marked by genetic variations that underscore the crucial role of genes in regulating cellular functions and interactions. Recognizing the significance of genetic factors in this context, this article delves into a genetic perspective, aiming to unravel the biological factors that govern the transition from one cell's fate to another within the hematopoietic system. To gain deeper insights into the genetic traits of three distinct blood cell types-HSCs, erythroblasts (EBs), and megakaryocytes (MKs)-we conducted a comprehensive transcriptomic analysis. Leveraging diverse hematopoietic cell datasets from healthy individuals, sourced from The BLUEPRINT consortium, our investigation targeted the identification of genetic variants responsible for changes in gene expression levels and epigenetic modifications across the entire human genome in each of these cell types. The total number of normalized expressed transcripts includes 14,233 novel trinity lncRNAs, 13,749 mRNAs, and 3092 lncRNAs. This scrutiny revealed a total of 31,074 transcripts, with a notable revelation that 14,233 of them were previously unidentified or novel lncRNAs, highlighting a substantial reservoir of genetic information yet to be explored. Examining their expression across distinct lineages further unveiled 2845 differentially expressed (DE) mRNAs and 354 DE long noncoding RNAs (lncRNAs) notably enriched among the three distinct blood cell types: HSCs, EBs, and MKs. Our investigation extended beyond mRNA to focus on the dynamic expression of lncRNAs, revealing a well-defined pattern that played a significant role in regulating differentiation and cell-fate specification. This coordination of lncRNA dynamics extended to aberrations in both mRNA and lncRNA transcriptomes within HSCs, EBs, and MKs. We specifically characterized lncRNAs with preferential expression in HSCs, as well as in various downstream differentiated lineage progenitors of EBs and MKs, providing a comprehensive perspective on lncRNAs in human hematopoietic cells. Notably, the expression of lncRNAs exhibited substantial cell-to-cell variation, a phenomenon discernible only through single-cell analysis. The comparative analysis undertaken in this study provides valuable insights into the distinctive genetic signatures guiding the differentiation of these crucial hematopoietic cell types.

Keywords:  hematopoiesis; hematopoietic lineages; lncRNAs; transcriptome

DOI:  https://doi.org/10.3390/ijms251810073