Search Results (167)

Erythropoiesis is a tightly regulated developmental process that requires the switch from fetal hemoglobin (HbF) to adult hemoglobin (HbA). In β-hemoglobinpathies such as SCD and β-thalassemia, disease severity is influenced by the fetal-to-adult hemoglobin switch because persistence or induction of HbF will ameliorate the clinical manifestations. miRNAs play an essential role in regulating this switch by modulating the expression levels of key transcription factors, such as BCL11A, KLF1, and MYB, which repress γ-globin expression. Multiple miRNAs have been identified as potential modulators of the hemoglobin switch, including miR-144, miR-486, miR-26b, and miR-15a. The molecular interactions between miRNA and γ-to β-globin switch have the potential for new therapeutic interventions that aim to reactivate HbF expression to ameliorate β-hemoglobinopathies such as SCD and β-thalassemia. In this review, the latest advancements in miRNA-mediated regulation of Hb switching and nanoparticle-based strategies for miRNA delivery are explored. Full article

Sickle cell disease is an autosomal recessive hemoglobin disorder affecting about 100,000 people in the United States, predominantly those of African descent. A point mutation in the β-globin gene in red blood cells causes these cells to sickle under hypoxemic conditions, reducing blood flow and oxygen delivery to tissues. This manifests in the form of painful vaso-occlusive episodes, acute chest syndrome, and acute infarction of various organs, including the spleen, bone, and lung. While sickle cell disease complications such as hemolytic anemia, tissue hypoxia, and chronic organ damage are well studied, attention to the unique reproductive challenges faced by patients with sickle cell disease remains underrecognized and underappreciated. This review aims to explore key reproductive health issues in patients with sickle cell disease, including diminished ovarian reserve, infertility, and obstetric and perinatal risk. Secondly, this review aims to identify key counseling and care opportunities for providers to support patients with sickle cell disease in meeting their reproductive goals. Full article

Haemoglobinopathies, including β-thalassaemia and sickle cell disease (SCD), are among the most common monogenic disorders worldwide and remain major causes of morbidity and early mortality. Historically, management of these life-altering diseases has relied on supportive treatment and symptom management and, although these treatments reduce symptoms and ease disease burden, they do not correct the underlying genetic defect. Allogenic haematopoietic stem cell transplantation (HSCT) has been the only established curative option; however, it comes with substantial risks that significantly restrict its applicability. Over the past two decades, haematopoietic stem cell (HSC) gene therapy for haemoglobinopathies has rapidly progressed from experimental proof-of-concept to approved therapies. Lentiviral gene addition approaches have demonstrated durable expression of functional β-like globin transgenes, achieving transfusion independence in β-thalassaemia patients and significant reductions in vaso-occlusive events in SCD patients. Alternative therapeutic approaches to promote HbF expression have proved to be highly successful. Gene silencing strategies targeting BCL11A have been successful clinically and, more recently, gene editing technologies such as CRISPR/Cas9 have enabled precise disruption of regulatory elements controlling γ-globin repression, leading to the approval of the first CRISPR-based therapy for SCD and β-thalassaemia. Emerging base editing technologies promise even more precise genetic modification and are advancing through clinical evaluation. Despite these advances, access to gene therapy remains restricted due to the need for highly specialised manufacturing, toxic myeloablative conditioning regimens, and high treatment costs. Ongoing improvements and adaptations in these areas are essential to ensure that gene therapies fulfil their potential as accessible, curative treatments for patients suffering from haemoglobinopathies worldwide. Full article

Background/Objectives: Thalassemia is an inherited blood disorder caused by defects in hemoglobin production, where an imbalance or reduction in globin-chain synthesis impairs normal red cell development and results in anemia of varying severity. The disease is classified into α-thalassemia and β-thalassemia according to the affected globin genes. In recent years, infrared (IR) Microspectroscopy has gained increasing attention for blood analysis because it is rapid, label-free, and capable of detecting subtle biochemical alterations. Method: In this study, we analyzed hemoglobin lysate collected from clinically characterized normal, carriers, and thalassemia patients (n = 333) using IR Microspectroscopy combined with multivariate statistical methods, including Principal Component Analysis (PCA) and Partial Least Squares Discriminant Analysis (PLS-DA). This approach enabled us to investigate how spectral features correspond to disease status across a range of genotypes commonly encountered in clinical practice. Results: Clear intergroup spectral differences were observed, and the classification models demonstrated diagnostic performance with sensitivity and specificity of approximately 80–90%. Because the technique is non-destructive, requires no chemical reagents, and allows direct biochemical profiling of hemoglobin, it offers practical advantages over conventional hematologic or molecular assays. Conclusions: These findings support the potential of IR-based spectral analysis as a complementary tool for thalassemia screening. Looking ahead, incorporating advanced machine learning algorithms with IR Microspectroscopy may further enhance early detection, improve risk stratification, and strengthen prevention and management strategies in routine clinical workflows. Full article

Pancreatic β-cells are metabolically active endocrine cells with a high oxygen demand to sustain glucose-stimulated insulin secretion (GSIS). Hypoxia, arising from vascular disruption, islet isolation, or pathological states such as type 2 diabetes (T2D) and obstructive sleep apnoea (OSA), is a potent metabolic stressor that impairs β-cell function, survival, and differentiation. At the molecular level, hypoxia-inducible factors (HIF-1α and HIF-2α) orchestrate transcriptional programs that shift β-cell metabolism from oxidative phosphorylation to glycolysis, modulate mitochondrial function, and regulate survival pathways such as autophagy and mitophagy. Crosstalk with nutrient-sensing mechanisms, redox regulation, growth factor signaling, and protein synthesis control further shapes adaptive or maladaptive outcomes. Hypoxia alters glucose, lipid, and amino acid metabolism, while mitochondrial dysfunction, oxidative stress, and inflammatory signaling contribute to progressive β-cell failure. Therapeutic strategies including incretin hormones, GABAergic signaling, erythropoietin, ChREBP inhibition, and activation of calcineurin–NFAT or oxygen-binding globins—offer potential to preserve β-cell viability under hypoxia. In islet transplantation, oxygen delivery technologies, ischemic preconditioning, mesenchymal stem cell–derived exosomes, and encapsulation systems show promise in mitigating hypoxic injury and improving graft survival. This review synthesizes current knowledge on β-cell responses to hypoxic stress, with emphasis on metabolic reprogramming, molecular signaling, and translational interventions, underscoring that targeted modulation of β-cell metabolism and oxygen handling can enhance resilience to hypoxia and improve outcomes in diabetes therapy and islet transplantation. Full article

Background/Objectives: Sickle cell disease (SCD) and β-thalassemia are autosomal recessive disorders of erythroid cells due to gene mutations occurring at the level of the β-globin gene. The severe forms of these hemoglobinopathies observed in individuals homozygous for these defective genes need intensive treatments, are associated with a poor quality of life, and allogeneic hematopoietic stem cell represents the only curative treatment option that can be offered to a limited proportion of patients. Methods: This work is a narrative review supported by a systematic literature search and analysis. Results: To bypass this limitation, autologous hematopoietic stem cell transplantation has been developed in these patients, in which patients’ HSCs are harvested and genetically modified ex vivo, then transplanted back into patients after conditioning for stem cell transplantation. There are two different approaches for gene therapy of hemoglobinopathies, one based on gene addition or gene silencing using lentiviruses as vectors and the other based on gene editing strategies using CRISPR-Caspase 9 technology or base editing. Several gene therapy products have been successfully evaluated in these patients, achieving transfusion independence and correction of hematological abnormalities durable over time. Conclusions: Several gene therapy products have been approved for the treatment of SCD and β-thalassemic patients and offer potentially curative treatment for these patients. Full article

Torque teno virus (TTV) is a highly prevalent DNA virus in humans, but its role in carcinogenesis is not well understood. While human papillomavirus (HPV) is a well-established etiological agent in cervical cancer, co-infections with other viruses such as Epstein–Barr virus (EBV) or TTV may influence disease progression. We conducted a cross-sectional study using 94 formalin-fixed, paraffin-embedded (FFPE) cervical tissue samples. These specimens were collected from women with cervical intraepithelial lesions (CINI-III) or squamous cell carcinoma (SCC) at the Clinical Hospital of the University of Chile. After extracting DNA, we screened for TTV using real-time polymerase chain reaction (qPCR). Statistical analysis was performed using Fisher’s exact test. Of the 94 samples, 83 were positive for the human β-globin gene and included in the final analysis. TTV was detected in 12.0% (10/83) of these samples. Among the TTV-positive cases, the virus was most frequently detected in high-grade lesions (70.0%), followed by low-grade lesions (20.0%) and squamous cell carcinoma (10.0%). However, these differences were not statistically significant (p = 0.688). This is the first study to assess TTV prevalence in cervical lesions among Chilean women. Although we found no statistically significant associations, a higher frequency of TTV was detected in precursor lesions compared to SCC. Further studies are needed to understand the potential immunomodulatory role of TTV in cervical carcinogenesis. Full article

Introduction: In hemoglobinopathies, the amount of globin synthesis in hemoglobin (Hb) or its structure is altered. Clinical features are related to the rate and kind of structural aberrations. The heterozygous form of the Lepore syndrome resembles minor thalassemia both clinically and hematologically. On electrophoresis, abnormal Hb Lepore fractions are found at a rate of 5–15%, with a mildly higher percentage of HbF and lower HbA. In general, Hb Lepore heterozygotes are asymptomatic. Case presentation: A 32-year-old male was admitted to our hospital with complaints of pain and swelling in multiple large joints and high-grade fever for 11 days. His past history was unremarkable; one of his sisters had the β-thalassemia trait. On physical examination, he was moderately anemic, with mild hepatomegaly and normal spleen; both knees and ankles were tender and swollen. Laboratory showed mild microcytic hypochromic anemia with variables similar to the thalassemia trait and signs of inflammation with very high CRP, serum ferritin, and leukocytosis. Blood sugars were increased. Hb electrophoresis showed an abnormal pattern with mild elevation in HbS, normal Hb F, mild reduction in HbA, and high HbA2, compatible with heterozygosity for the Hb Lepore beta chain variant. He was initially diagnosed with diabetes (treated with insulin) and sepsis from unknown origin, but fever and joint pains did not respond to NSAIDs or antibiotics. He had very good response on high-dose methylprednisolone. Undifferentiated arthritis was diagnosed in the patient with Hb Lepore, and he was treated with oral prednisolone and sulfasalazine (SSZ). At follow up, the patient was doing well. He refused further investigations and did not allow testing on his family members. In summary: Hb Lepore is a rare hemoglobinopathy linked to thalassemia, which may manifest with musculoskeletal problems. Our patient with the Hb Lepore trait presented with undifferentiated polyarthritis and fever, but in our case, a causal relationship remains unclear. This is one of the first adult cases of Hb Lepore in Bangladesh and the first with arthritis of unknown origin. The prevalence of Hb Lepore in Bangladesh is unknown. Full article

Background/Objectives: Thalassemia comprises a group of heterogeneous hereditary hemoglobinopathies characterized by impaired hemoglobin synthesis due to mutations in the α, β, and/or δ globin genes. The resulting ineffective erythropoiesis produces anemia of variable severity depending on the affected globin chain. Although β-thalassemia is most prevalent in the Mediterranean region, the Middle East, and Southeast Asia, migration has contributed to its global spread, including in non-endemic areas. In Chile, published data on β-thalassemia trait (BTT) and β-thalassemia major (BTM) remain scarce. This study aimed to estimate the frequency of BTT in referred outpatients to a clinical laboratory in southern Chile. Methods: A retrospective observational study was conducted between January 2021 and November 2024 at a clinical laboratory in Puerto Montt. Complete Blood Cell counts (CBCs) from unique patients were reviewed, and those confirmed with confirmed thalassemia (HbA2 > 3.5%) were selected. Results: During the study period, 24,634 CBCs were reviewed. Sixty patients were confirmed as carriers of BTT, corresponding to a frequency of 0.24% (CI 95%: 0.18–0.31%) in the referred outpatients to laboratory (60/24,634). This occurrence is higher than the only previously published Chilean estimate but lower than frequencies reported in several South American countries. Conclusions: This investigation demonstrates a relatively low but non-negligible frequency of BTT in outpatients from southern Chile. The findings emphasize the importance of considering BTT in the differential diagnosis of microcytic anemia, a condition often underestimated in routine practice. Broader multicenter studies across Chile are warranted to validate these results and to provide a clearer picture of the epidemiology of β-thalassemia in the country. Full article

Background: Haemoglobinopathies are among the most common monogenic disorders worldwide. Early identification of asymptomatic carriers through reliable screening and molecular diagnostics is crucial for prevention programmes, especially in high-prevalence regions such as Southern Italy. Methods: A total of 5243 individuals were analysed between 2013 and 2024 using both biochemical and genetic parameters. First-level screening included full blood count, iron status, and high-performance liquid chromatography (HPLC) for haemoglobin variant quantification. Molecular analyses were performed using next-generation sequencing (NGS) for the HBA1, HBA2, and HBB genes. Results: We identified 267 individuals (11.2%) as carriers of α-thalassaemia and 473 individuals (16.7%) as carriers of β-thalassaemia. Among them, 5 were compound heterozygotes and 3 homozygous for the α-3.7 deletion. A rare case of HbG Philadelphia in association with a triplicated α-gene was also observed. The most common β-globin mutations included c.118C>T (β⁰39, 44%), IVS-I-110 (17.7%), IVS-I-6 (12.7%), and IVS-I-1 (12.3%). Among α-globin mutations, the most prevalent were -α^3.7 (48%), α2 IVS1 -5nt (15.4%), -20.5 Kb (14.2%), and triplicated α (11%). In total, 18.7% of individuals were found to carry either α- or β-thalassaemia traits. Conclusion: Our findings highlight the limitations of traditional diagnostic methods—such as the osmotic fragility test—and the importance of integrating haematological, biochemical, and molecular data to accurately identify thalassaemia carriers. The variability of genotype–phenotype correlations, especially in the context of immigration and genetic diversity, underscores the need for comprehensive molecular analysis. We propose a three-step diagnostic algorithm combining first-level screening, iron status assessment, and NGS-based sequencing for inconclusive cases. Full article

β-thalassemia is an inherited blood disorder caused by mutations in the β-globin (HBB) gene, leading to reduced or absent β-globin production, resulting in chronic anemia. While current therapies, including blood transfusions and hematopoietic stem cell transplantation, offer symptomatic relief, they are limited by complications and their limited accessibility. CRISPR-based gene editing technologies provide new therapeutic avenues by enabling the precise correction of HBB mutations or the reactivation of fetal hemoglobin (HbF) through the targeting of regulatory elements such as BCL11A. These approaches have shown promising preclinical and clinical outcomes. However, efficient and safe delivery remains a major challenge. Viral vectors offer high efficiency but raise concerns about immunogenicity and insertional mutagenesis, whereas non-viral systems such as lipid nanoparticles and engineered exosomes offer lower toxicity and modularity but face targeting limitations. This review highlights recent progress in CRISPR-based therapies for β-thalassemia and emerging delivery strategies to enhance clinical translation. Full article

β-thalassemia is a chronic genetic blood disorder characterized by defective β-globin synthesis, requiring frequent transfusions and resulting in iron overload, immune dysfunction, and increased susceptibility to infections. In these immunocompromised patients, altered immune responses lead to significant changes in the human virome, promoting viral persistence, reactivation, and expansion of pathogenic viral communities. This review explores the intricate relationship between β-thalassemia and the human virome, focusing on how clinical interventions and immune abnormalities reshape viral dynamics, persistence, and pathogenicity. Patients with β-thalassemia exhibit profound innate and adaptive immune dysregulation, including neutrophil dysfunction, T cell senescence, impaired B cell and NK cell activity, and expansion of myeloid-derived suppressor cells. These alterations create an immunological niche that favors viral reactivation and virome expansion. Iron overload enhances viral replication, while chronic transfusions introduce transfusion-transmitted viruses. Splenectomy and allo-HSCT further compromise viral surveillance. Additionally, disruptions in the gut virome, particularly bacteriophage-driven dysbiosis, may exacerbate inflammation and impair host–virus homeostasis. The human virome is not a passive bystander but a dynamic player in the pathophysiology of β-thalassemia. Understanding virome–immune interactions may offer novel insights for infection monitoring, risk stratification, and precision therapies in thalassemic patients. Full article

Variants of uncertain significance (VUS) are often challenging for genetic counseling and require additional data for accurate variant classification. This study aims to describe the genotype-phenotype correlation of the seven β-globin gene variants found in Thailand. Retrospective data in a total of 45,914 subjects encountered at our diagnostic laboratory from January 2012 to December 2024 were reviewed. A total of 33 leftover EDTA blood specimens, suspected of having β-globin gene defects, were included. Eighty-nine normal subjects were also analyzed to confirm phenotypic expression of the variants. The whole β-globin and Krüppel-like factor 1 (KLF1) genes were examined using PCR-based methods. Seven nucleotide variants were identified among 33 suspected subjects, including a novel (β^−206(C>G)), four hitherto undescribed in Thailand [β^−198(A>G), β^{IVSII−180(T>C)}, β^{IVSII−337(A>G)}, and β^*233(G>C)], and two known variants [β^−50(G>A) and β^{IVSII−258(G>A)}]. The β^−198(A>G) and β^*233(G>C) variants were also identified in 1.69% of normal subjects, indicating neutral DNA polymorphisms. All subjects of β^−198(A>G), β^{IVSII−180(T>C)}, β^{IVSII−258(G>A)}, and β^{IVSII−337(A>G)} with borderline Hb A₂ levels had KLF1 mutations. Compound heterozygous β^−206(C>G) and known β⁺-thalassemia trait revealed β-thalassemia trait phenotype. In silico pathogenicity prediction showed that the β^−206(C>G), β^−198(A>G), β^{IVSII−180(T>C)}, β^{IVSII−258(G>A)}, β^{IVSII−337(A>G)}, and β^*233(G>C) were associated with benign variants. It was found that heterozygous β^−50(G>A) had elevated Hb A₂ levels resembling those of β-thalassemia trait. However, the association of the β^−50(G>A) and Hb E or β-thalassemia revealed a phenotype of Hb E or β-thalassemia trait. Most prediction tools indicate that the β^−50(G>A) is associated with benign variants; however, PromoterAI revealed that the β^−50(G>A) is associated with under-expression of the β-globin gene with high sensitivity. Based on these findings, the β^−50(G>A) is most likely a very mild β⁺-thalassemia allele. This study described the genotype-phenotype correlation of known and novel β-globin gene variants found in Thailand. The data should prove useful for accurate variant classification, genetic counseling, and a prevention and control program of severe thalassemia diseases in Thailand. Full article

Sickle cell disease (SCD) is the most common hemoglobinopathy, caused by a mutation in the β-globin gene of hemoglobin. It predisposes patients to painful Vaso-occlusive crises (VOC) and multi-organ dysfunctions. The disease exhibits significant phenotypic variability, making it challenging to predict severity and outcomes. This study aimed to characterize the whole blood gene expression profile of Bahraini SCD patients, identifying differentially expressed genes during steady-state (n = 10) and VOC (n = 10) compared to healthy controls (n = 8). Analysis revealed 2073 and 3363 dysregulated genes during steady-state and VOC, respectively, compared to controls, with 1078 genes differentially expressed during VOC versus steady-state. Gene Ontology (GO) enrichment analysis highlighted significant deregulation in immune and hematopoietic pathways, including down-regulation of critical genes for immune modulation and hematopoietic balance. Notably, the transcription factor RUNX3, involved in immune cell differentiation and inflammation, was among the 668 down-regulated genes. RUNX3 was four-fold down-regulated in microarray analysis, three-fold in PCR, and showed a mean protein concentration of 11.13 pg/mL during VOC compared to 457.93 pg/mL during steady-state (p < 0.01). These findings suggest that RUNX3 may serve as a potential biomarker for VOC. Future large-scale validation, additional proteomic studies, and functional investigations are recommended to confirm its clinical utility and significance. Full article

Sickle-cell disease (SCD) is a group of inherited blood disorders in which a mutation in the β-globin (HBB) gene causes red blood cells to produce abnormal hemoglobin, known as Hb S. SCD is characterized by an autosomal-recessive pattern of inheritance, implying that for a child to manifest the condition, they must inherit an Hb S allele from both parents (HbSS) or one Hb S allele and another β-globin variant, such as Hb C or β-thalassemia (HbSC, HbS/β-thal). It has been observed that (heterozygote) carriers of one copy of the sickle-cell trait (HbAS) are typically healthy and can even gain partial protection from severe malaria. The term “severe and complicated malaria” is delineated based on specific clinical and laboratory characteristics in the presence of Plasmodium falciparum parasitemia. The prevalent forms of severe malaria among African children include cerebral malaria, respiratory distress, and severe malaria anemia. Cerebral malaria is a rare complication of malaria infection and is associated with a high mortality rate. Full article