RARE DISEASE
Beta-thalassemia intermedia
Beta-thalassemia intermedia
Beta-thalassemia intermedia
Drug discovery
7
drugs
With orphan designations
Overview
Beta-thalassemia intermedia (BTI) is a non-transfusion-dependent hemoglobinopathy characterized by moderate anemia (Hb 7–10 g/dL) due to impaired β-globin synthesis. Symptoms range from asymptomatic to complications such as extramedullary hematopoiesis, skeletal deformities, iron overload (even without transfusions), thrombotic events, and pulmonary hypertension. Management includes tailored transfusions, hydroxyurea to induce fetal hemoglobin, iron chelation, and splenectomy in select cases [1][3][4][13].
Burden
Morbidity: Osteoporosis, leg ulcers, hepatosplenomegaly, and thromboembolism (↑ risk post-splenectomy) [4][13][14].
Mortality: Primarily from cardiac iron overload, pulmonary hypertension, or thrombotic events [5][13][15].
Quality of life: Impacted by chronic pain, growth delays, and endocrine dysfunction [9][14][16].
Therapies
Transfusions: Episodic use for anemia exacerbations, growth failure, or pregnancy [1][3].
Hydroxyurea: Reduces transfusion needs by boosting fetal hemoglobin (HbF) [3][11].
Iron chelation: Required for iron overload from chronic transfusions or increased intestinal absorption [5][13].
Splenectomy: Reserved for severe hypersplenism or transfusion-refractory anemia [4][11].
Categories: rare endocrine diseases, rare genetic diseases, rare hematological diseases, rare renal diseases, rare transplant-related disorders
Research Papers
464 drug discovery papers about Beta-thalassemia intermedia, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
464 drug discovery papers about Beta-thalassemia intermedia, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-09 | Safety and Effectiveness of Thalidomide in Transfusion-Dependent and Non-Transfusion-Dependent Thalassaemia Children in Eastern India.
Thalassaemia is a major public health concern in Eastern India, with many children requiring lifelong blood transfusions. Thalidomide, known for its immunomodulatory properties, has shown promise in reducing transfusion needs by increasing fetal hemoglobin production.The safety and efficacy of thalidomide was evaluated in 404 patients aged 2 to 18 years, diagnosed with beta thalassaemia major or intermedia.Mean age was 8.4 years with 54.5 % cases being male. Majority of the patients were Beta thalassaemia major (54.8%). Mean Haemoglobin ± SE at baseline was 6.435 ± 0.092, with a significant increase in haemoglobin levels from 6.435 ± 0.092 at baseline to 8.157 ± 0.069 at the 12 months (p < 0.001). The mean number of transfusions decreased from 1.261 ± 0.051 at 3 months to 1.108 ± 0.074 at 12 months (p < 0.001). The mean spleen size decreased from 3.712 ± 0.087 at baseline to 2.242 ± 0.068 at 12 months (p < 0.001). The mean ferritin level decreased from 1947 ng/mL at baseline to 1554 ng/mL at 12 months (p < 0.001). This decline in ferritin reflects both reduced transfusion requirements and improvement in iron overload. Total bilirubin levels also showed a significant downward trend over 12 months (p < 0.001). At the end of 12 months, 30.7% of the responses were excellent, 52.5% were good, 13.3% were partial and rest 3.5% were no response. Side effects were reported in 62.6% of the patients, out of which most common was constipation (51%).Thalidomide significantly benefits transfusion-dependent thalassaemia patients, with a high proportion showing excellent or good response.
2026-07-22 | Management of nontransfusion dependent thalassemia (NTDT)
Introduction: Nontransfusion dependent Thalassemia (NTDT) like E-beta thalassemia and -thalassemia intermedia are the most common Thalassemia syndrome in India. As compared to transfusion dependent Thalassemia (TDT), Non Transfusion Dependent Thalassemia (NTDT) does not require regular and frequently packed RBC transfusion to prevent anemia related complications. Still NTDT subjects may suffer from the complications of Iron overload due to ineffective erythropoesis and increased intestinal iron absorption. Hydroxyurea therapy which reduces transfusion requirement by raising fetal Hb level and early iron chelation therapy to reduce Liver Iron Concentration (LIC) are mainstay of management in NTDT.Objectives: To study the clinico -hematological profile and management of Non Transfusion Dependent Thalassemia (NTDT)Results: Total 21 children of Non Transfusion Dependent Thalassemia (receiving
2026-02-23 | Pulmonary hypertension in beta thalassemia: a prospective cohort study on treatment outcomes and cardiopulmonary function.
Beta thalassaemia, an inherited blood disorder, exhibits a broad range of phenotypes from asymptomatic to severe anaemia. Pulmonary hypertension (PH) is a major complication in thalassaemia patients, significantly impacting morbidity and mortality. This study aimed to assess the clinical condition of thalassaemia patients with PH over the course of one year while receiving treatment in accordance with the guidelines of the European Society of Cardiology (ESC). A prospective cohort study was carried out at Rohani Hospital in Iran from May 2020 to May 2021. The study included patients diagnosed with beta thalassaemia intermedia who also had PH confirmed by echocardiography. Treatment was administered according to ESC guidelines, incorporating vasodilators and other supportive medications. Clinical and laboratory data were gathered, and statistical analyses were conducted. Nineteen patients, with a mean age of 42.57 ± 8.62 years, participated in the study. Treatment resulted in notable improvements in the 6-minute walk test (6MWT) (p < 0.001), reduced proBNP levels (p = 0.016), and a lower E/e' ratio (p = 0.01), suggesting enhanced right ventricular (RV) function. However, there were no significant changes in pulmonary artery pressure (PAP) or RV size. Additionally, repeated blood transfusions were linked to RV dysfunction. Repeated blood transfusions correlate with RV dysfunction in thalassaemia patients with PH. Vasodilatory treatment improves 6MWT, proBNP levels, and E/e' ratio, indicating RV function enhancement. This study underscores the importance of comprehensive management strategies for thalassaemia patients with PH to mitigate associated complications and improve outcomes.
2025-10-30 | Beta-Thalassemia Intermedia in Disguise: A Case of Delayed Diagnosis in a Child with Persistent Cytopenias
Aplastic anemia and thalassemia are two distinct hematological disorders that are rarely seen in combination. This report describes the case of a 7-year-old boy initially diagnosed with aplastic anemia based on clinical and bone marrow findings, who was later found to have coexistent beta-thalassemia intermedia. The patient presented with chronic pallor, fatigue, gum bleeding, and growth retardation, along with persistent thrombocytopenia since age two. Despite multiple platelet transfusions, steroids, and splenectomy, there was no sustained improvement. Subsequent marrow biopsy confirmed aplastic anemia, and treatment with oxymetholone and cyclosporine was initiated. Persistent anemia led to hemoglobin electrophoresis, revealing elevated HbF (24.3%) and confirming beta-thalassemia intermedia. After treatment with thalidomide and hydroxyurea, his transfusion requirements markedly decreased, with the last transfusion in March 2024. This case underscores the diagnostic complexity of overlapping hematologic disorders, particularly in regions with high thalassemia prevalence. Early utilization of hemoglobin electrophoresis in unexplained or refractory cytopenias can help avoid misdiagnosis and guide timely, effective treatment.
2025-08-07 | Therapeutic Response to Hydroxyurea in Beta-Thalassemia Intermedia with Rare Mutation: A Case Report.
Beta-thalassemia is a hereditary hemoglobinopathy characterized by significant clinical variability, largely influenced by the underlying genetic mutations. We report a 47-year-old female patient with β-thalassemia intermedia harboring a rare homozygous mutation in the β-globin gene promoter: HBB:c.-136C > G (-86 C > G). The patient showed marked clinical response to hydroxyurea therapy with a notable increase in hemoglobin levels, reduction in spleen size and improvement of fatigue and bone pain due to extramedullary hematopoiesis. This report highlights the role of genetic characterization in understanding rare forms of thalassemia and the potential of hydroxyurea as a personalized treatment strategy for patients with unique genetic determinants.
cell therapies
2024-12-31 | Hemolysis due to anti-IH in a patient with beta-thalassemia and Mycoplasma pneumoniae infection.
Anti-IH is a common cold agglutinin that is typically clinically insignificant. We present a case that resulted in hemolysis. A 32-year-old male patient with transfusion-independent beta-thalassemia intermedia presented with symptomatic anemia. His blood sample typed as group B, D+ and demonstrated multiple alloantibodies and cold autoantibodies. He was transfused uneventfully, but re-presented 10 days later with recurrent, worsening anemia. At this time, transfusion of group O, phenotype-matched red blood cells (RBCs) resulted in an acute hemolytic reaction. While anemia was initially attributed to drug-mediated bone marrow toxicit y and subsequently to a delayed hemolytic reaction, further evaluation revealed Mycoplasma pneumoniae infection and a cold agglutinin (anti-IH specificity), indicating a likely autoimmune-mediated anemia due to an infectious etiology. Subsequent transfusion of 2 group B, phenotype-matched RBC units using a blood warmer was uneventful. Anti-IH is only rarely associated with hemolytic transfusion reactions, which may be exacerbated when transfusing group O RBC units to group B patients. M. pneumoniae infection likely led to cold agglutinin-mediated hemolysis of endogenous and transfused RBCs. The patient was successfully managed with intravenous immunoglobulin, steroids, rituximab, erythropoietin, hydroxyurea, and amoxicillin clavulanate/azithromycin. This case illustrates the importance of infectious disease evaluation in patients with unexplained anemia, the potential clinical significance of autoanti-IH, and the value of providing type-specific RBC units in these circumstances.
2024-10-01 | Integrated metabolomic and microbiome analysis identifies Cupriavidus metallidurans as a potential therapeutic target for β-thalassemia.
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.
2021-03-16 | Longitudinal follow-up of patients with thalassaemia intermedia who started transfusion therapy in adulthood: a cohort study.
We longitudinally evaluated the effects of regular blood transfusions (BTs), in the real-life context of the Myocardial Iron Overload in Thalassaemia network, in patients with thalassaemia intermedia (TI). We considered 88 patients with TI (52 females) who started regular BTs after the age of 18 years. Magnetic resonance imaging was used to quantify iron overload and biventricular function. For 56·8% of the patients there were more than two indications for the transition to regular BTs, with anaemia present in 94·0% of the cases. A significant decrease in nucleated red blood cells, platelets, lactate dehydrogenase, bilirubin, and uric acid levels was detected 6 months after starting regular BTs. After the transition to the regular BT regimen there was a significant increase only in the frequency of hypothyroidism and osteopenia, and a significant decrease in liver iron and cardiac index. The percentage of chelated patients increased significantly after starting regular BTs. The decision to regularly transfuse patients with TI may represent a way to prevent or slow down the natural progression of the disease, despite the more complex initial management.
2021-03-01 | Red Blood Cell Exchange in a Patient With Extramedullary Hematopoiesis and Cor Pulmonale Secondary to Beta Thalassemia
Rationale: Beta thalassemia is a congenital defect in the production of the beta globin chain. Patients with beta thalassemia major will have higher levels of hemoglobin F (HbF), which is suboptimal in releasing oxygen to tissue. Herein, we describe the use of red blood cell (RBC) exchange transfusion, a therapy typically used in sickle cell patients, in the management of a patient with beta thalassemia with extensive extramedullary hematopoiesis and elevated levels of HbF. Patient concerns: A 34-year-old male of mixed African American and Southeast Asian descent with a known history of beta thalassemia major presented with progressive dyspnea on exertion with marked fatigue. Diagnoses: The patient was transferred to our facility for management of acute hypoxemic, hypercapnic respiratory failure associated with cor pulmonale. Interventions: The patient was initially managed with non-invasive positive pressure support ventilation (NIPPV) and intravenous diuresis. Hydroxyurea and epoprostenol nebulization were added to his treatment regimen; however, he progressively became more unstable, necessitating inotropic support. With extramedullary hematopoiesis leading to mass-like effect on critical organs and very high HbF (96%) thought to contribute to his presentation, red blood cell exchange transfusion was initiated once the blood pressure stabilized. Outcomes: The patient clinically improved, and was discharged home within a week on supplemental oxygen by nasal cannula and long-term red blood cell exchange. Lessons: We postulated that significantly elevated HbF contributed to the patient’s chronic hypoxia and subsequent respiratory complications. Based on the patient's clinical improvement following the intervention, we believe that RBC exchange transfusion could be considered in the management of beta thalassemia patients with significantly elevated levels of HbF.
2019-01-01 | Red blood cell alloimmunisation in transfusion-dependent thalassaemia: a systematic review.
Chronic red blood cell transfusion is the first-line treatment for severe forms of thalassaemia. This therapy is, however, hampered by a number of adverse effects, including red blood cell alloimmunisation. The aim of this systematic review was to collect the current literature data on erythrocyte alloimmunisation.We performed a systematic search of the literature which identified 41 cohort studies involving 9,256 patients.The prevalence of erythrocyte alloimmunisation was 11.4% (95% CI: 9.3-13.9%) with a higher rate of alloimmunisation against antigens of the Rh (52.4%) and Kell (25.6%) systems. Overall, alloantibodies against antigens belonging to the Rh and Kell systems accounted for 78% of the cases. A higher prevalence of red blood cell alloimmunisation was found in patients with thalassaemia intermedia compared to that among patients with thalassaemia major (15.5 vs 12.8%).Matching transfusion-dependent thalassaemia patients and red blood cell units for Rh and Kell antigens should be able to reduce the risk of red blood cell alloimmunisation by about 80%.
proteins
2025-10-20 | Expression of the FAM132B Gene in Iranian Patients with Beta-Thalassemia
Background: Iron homeostasis is a complex process involving multiple factors. Erythroblasts secrete erythroferrone (ERFE), which affects hepcidin production, thereby enhancing iron uptake. This study aimed to investigate the expression of the ERFE-encoding FAM132B gene in Iranian patients with beta-thalassemia major (BTM) and beta-thalassemia intermedia (BTI). Materials and Methods: A total of 40 BTM and BTI patients and 20 healthy blood donors as a control group were recruited. Total RNA was extracted from whole blood samples, and cDNA was synthesized. Gene expression was quantified using a SYBR Green-based real-time PCR (RT-PCR) assay. Data analysis was performed by the GraphPad Prism program using the one-way ANOVA test. Results: The expression of the FAM132B gene was upregulated in BTI patients compared to BTM patients (p = 0.0151). Despite the higher mRNA fold change in BTI patients, no significant difference was observed in the FAM132B gene expression between beta-thalassemia patients (major and intermedia) and the control group. Conclusion: The expression of the FAM132B gene was different between beta-thalassemia major and intermedia patients. Further studies should be conducted to better elucidate the role of erythroferrone as a potential therapeutic target in patients with beta-thalassemia.
2024-02-08 | Beta-Thalassemia: A Pharmacological Drug-Based Treatment
This review was performed to determine the potential of drugs that can remove or decrease the requirements for blood transfusion among beta (β)-thalassemia patients. A comprehensive literature search was conducted to identify clinical trials and studies using PubMed Central, Google Scholar, PubMed, and ScienceDirect archived articles published from 1996 to November 2023. According to this review, clinical trials for a number of drugs, including luspatercept, sotatercept, mitapivat, etavopivat, hydroxyurea, rapamycin, decitabine, thalidomide, and quercetin, have been performed as part of efforts to improve the cure strategy for β-thalassemia. Of these drugs, luspatercept and sotatercept have exhibited particularly promising results and have been granted US Food and Drug Administration (FDA) approval for use in β-thalassemia patients. The mode of action for the drugs luspatercept and sotatercept involves the stimulation of hemoglobin (Hb) production or enhancement of its functionality, thereby decreasing reliance on blood transfusions and enhancing the overall quality of life. In this way, drugs like luspatercept and sotatercept present an opportunity to notably decrease the necessity for blood transfusions in β-thalassemia patients, improving their standard of living and overall prognosis. However, more research is needed to evaluate the effectiveness and safety of these drugs in the long run.
2024-02-06 | BMI1 regulates human erythroid self-renewal through both gene repression and gene activation
Abstract The limited proliferative capacity of erythroid precursors is a major obstacle to generate sufficient numbers of in vitro-derived red blood cells (RBC) for clinical purposes. We and others have determined that BMI1, a member of the polycomb repressive complex 1 (PRC1), is both necessary and sufficient to drive extensive proliferation of self-renewing erythroblasts (SREs). However, the mechanisms of BMI1 action remain poorly understood. BMI1 overexpression led to 10 billion-fold increase BMI1-induced (i)SRE self-renewal. Despite prolonged culture and BMI1 overexpression, human iSREs can terminally mature and agglutinate with typing reagent monoclonal antibodies against conventional RBC antigens. BMI1 and RING1B occupancy, along with repressive histone marks, were identified at known BMI1 target genes, including the INK-ARF locus, consistent with an altered cell cycle following BMI1 inhibition. We also identified upregulated BMI1 target genes with low repressive histone modifications, including key regulator of cholesterol homeostasis. Functional studies suggest that both cholesterol import and synthesis are essential for BMI1-associated self-renewal. These findings support the hypothesis that BMI1 regulates erythroid self-renewal not only through gene repression but also through gene activation and offer a strategy to expand the pool of immature erythroid precursors for eventual clinical uses.
2019-01-08 | Luspatercept improves hemoglobin levels and blood transfusion requirements in a study of patients with β-thalassemia
Abstract β-thalassemia is a hereditary disorder with limited approved treatment options; patients experience anemia and its complications, including iron overload. The study aim was to determine whether luspatercept could improve anemia and disease complications in patients with β-thalassemia. This open-label, nonrandomized, uncontrolled study consisted of a 24-week dose-finding and expansion stage (initial stage) and a 5-year extension stage, currently ongoing. Sixty-four patients were enrolled; 33 were non–transfusion dependent (mean hemoglobin, <10.0 g/dL; <4 red blood cell [RBC] units transfused per 8 weeks), and 31 were transfusion dependent (≥4 RBC units per 8 weeks). Patients received 0.2 to 1.25 mg/kg luspatercept subcutaneously every 21 days for ≥5 cycles (dose-finding stage) and 0.8 to 1.25 mg/kg (expansion cohort and 5-year extension). The primary end point was erythroid response, defined as hemoglobin increase of ≥1.5 g/dL from baseline for ≥14 consecutive days (without RBC transfusions) for non–transfusion-dependent patients or RBC transfusion burden reduction ≥20% over a 12-week period vs the 12 weeks before treatment for transfusion-dependent patients. Eighteen non–transfusion-dependent patients (58%) receiving higher dose levels of luspatercept (0.6-1.25 mg/kg) achieved mean hemoglobin increase ≥1.5 g/dL over ≥14 days vs baseline. Twenty-six (81%) transfusion-dependent patients achieved ≥20% reduction in RBC transfusion burden. The most common grade 1 to 2 adverse events were bone pain, headache, and myalgia. As of the cutoff, 33 patients remain on study. In this study, a high percentage of β-thalassemia patients receiving luspatercept had hemoglobin or transfusion burden improvements. These findings support a randomized clinical trial to assess efficacy and safety. This study was registered at www.clinicaltrials.gov as #NCT01749540 and #NCT02268409.
2019-01-04 | A computational model to understand mouse iron physiology and disease
It is well known that iron is an essential element for life but is toxic when in excess or in certain forms. Accordingly there are many diseases that result directly from either lack or excess of iron. Yet many molecular and physiological aspects of iron regulation have only been discovered recently and others are still elusive. There is still no good quantitative and dynamic description of iron absorption, distribution, storage and mobilization that agrees with the wide array of phenotypes presented in several iron-related diseases. The present work addresses this issue by developing a mathematical model of iron distribution in mice calibrated with ferrokinetic data and subsequently validated against data from mouse models of iron disorders, such as hemochromatosis, β-thalassemia, atransferrinemia and anemia of inflammation. To adequately fit the ferrokinetic data required inclusion of the following mechanisms: a) transferrin-mediated iron delivery to tissues, b) induction of hepcidin by transferrin-bound iron, c) ferroportin-dependent iron export regulated by hepcidin, d) erythropoietin regulation of erythropoiesis, and e) liver uptake of NTBI. The utility of the model to simulate disease interventions was demonstrated by using it to investigate the outcome of different schedules of transferrin treatment in β-thalassemia.
gene therapies
2026-02-27 | Systematic Review of Non-Coding Genomic Variants in Globin and Non-Globin Clusters and Their Impact on Phenotypic Severity in Thalassemia and Sickle Cell Disease.
Background: Haemoglobinopathies such as beta-thalassemia (β-thal), alpha-thalassemia (α-thal) and sickle cell disease (SCD) are characterised by pathogenic gene variations (mutations) in the globin genes. Patients with haemoglobinopathies have the same disease-causing coding variations with very different disease phenotypes, from requiring blood transfusions to being non-symptomatic. The gap between the expected clinical outcomes based on primary coding mutations (the genotype) and the actual observed symptoms (the phenotype) often remains unexplained. We refer to the contribution of secondary genetic modifiers-specifically, non-coding variants of the genome that alter globin gene expression and pathophysiology-as the "missing heritability" of the clinical presentation [Primary Mutation + Missing Heritability (Non-Coding Variants) = Actual Clinical Phenotype]. Objectives: This systematic review aims to find evidence connecting genetic differences outside of the protein-coding region, as in promoters, enhancers or untranslated regions (UTRs), to the clinical severity (phenotype) of beta-thalassemia, alpha-thalassaemia and SCD. We summarise the molecular basis of phenotypic variation among haemoglobinopathy patients with identical variations to reveal their missing heritability and to enhance our understanding of prognostic strategies. Methods: This systematic review was performed in accordance with the PRISMA 2020 guidelines. We used search terms related to haemoglobinopathies, non-coding variation, SNP, promoters, enhancers and clinical severity to search major databases (PubMed and Google Scholar) as of October 2025. A total of 527 (out of 572) abstracts were fit for initial screening to identify the eligible reports. Due to heterogeneity in study designs and reported outcomes, findings were synthesised descriptively and grouped by variant mechanism (cis-acting and trans-acting). The final analysis included 89 articles that demonstrated a direct association between a non-coding genomic variant and a quantitative measure of clinical severity. Results: Two main groups of non-coding variants (NCVs) that modulate foetal haemoglobin (HbF) induction were identified. The first major group comprises cis-acting variants within globin gene clusters (HBG2 promoter XmnI polymorphism, HBB promoter mutations and α-globin enhancer variants), while the second major group comprises trans-acting quantitative trait loci (QTLs) (BCL11A and HBS1L-MYB loci). Non-globin NCVs in the UGT1A1 promoter were also found to influence the severity measures in β-thal and SCD. NCVs primarily alter the binding of transcription factors and the looping dynamics of chromatin, modulating the α/β chain balance ratio and γ-globin repression. The XmnI polymorphism is the most prominent cis-acting modifier associated with β-thal intermedia. The promoter polymorphisms in TNF-α and VCAM1 are associated with vascular complications in SCD. Conclusions: NCVs are fundamental when determining the clinical measures of haemoglobinopathies, in addition to coding variants. NCV screening should be integrated for clinical prognosis for the accurate prediction of haemoglobinopathy severity and associated high-risk complications. NCVs may represent promising targets for next-generation gene editing and therapeutic intervention strategies aimed at modifying the severity of β-thal, α-thal and SCD.
2025-03-31 | Treatment Options for Beta-Thalassemia
Beta-thalassemia, a hereditary blood disorder caused by point mutations affecting beta-globin synthesis, impairs erythrocyte oxygen transport. Due to its resistance, beta-thalassemia originally propagated in regions with high malaria prevalence. More recently, it has spread globally through human migration, impacting millions. Early screening of beta-thalassemia can be preconception, fetal, and infant testing and is vital for diagnosis and treatment plans. The types major, minor, and intermedia are classified based on their respective mutations and result in various symptoms ranging in severity. Regular erythrocyte transfusions replace faulty blood cells to treat thalassemia major. These transfusions cause iron overload, a severe side effect that is often treated with chelation therapy. Currently, the only cure for beta-thalassemia is hematopoietic stem cell transplantation. Hematopoietic stem cells are undifferentiated cells in the red bone marrow that proliferate and differentiate into various blood cells, including erythrocytes. Transplantation replaces deleterious hematopoietic stem cells with healthy ones that can differentiate into erythrocytes with full oxygen-carrying capacity. While an effective cure, there are many challenges pre-transplantation and post-transplantation; for example, finding suitable donors and preventing complications. Through medical advances in stem cell exploration and gene editing techniques, research continues to progress and discover potential cures. CRISPR-Cas, a prominent gene editing tool, has found success in identifying and modifying specific gene sequences. Researchers hope to apply CRISPR-Cas to the beta-globin synthesis gene and prevent beta-thalassemia. As technology advances, the practical and ethical challenges of accessibility, cost, and safety persist at the forefront of patient care.
2023-09-20 | Global Trends on β-thalassemia Research over 10 Years: A Bibliometric Analysis
Abstract Introduction Thalassemia, an inherited quantitative globin disorder, is the most prevalent monogenic disease globally. While severe alpha thalassemia results in intrauterine death, β-thalassemia manifests during childhood due to the "second conversion of hemoglobin," garnering increased attention in recent decades. Methods In this study, a bibliometric analysis will be conducted of thalassemia articles published in the Web of Science Core Collection database between 2013 and 2023 to establish a comprehensive overview and to identify emerging trends. A total of 5655 studies published between 2013 and 2023 were systematically retrieved, and annual publications demonstrated a steady increase, maintaining a high level over the past decade. Results The United States contributed the highest number of publications, followed by China. Notably, the journal Blood emerged as the leading authority in β-thalassemia research. Analysis of research hotspots revealed that the pathogenesis of β-thalassemia is primarily linked to iron overload, anemia, gene mutations, and ineffective erythropoiesis. Furthermore, recent studies focusing on gene editing therapies present promising avenues for future investigation. Conclusion These findings grasp the research status of β-thalassemia and shed new light on future research frontiers.
2023-06-28 | An Expert Overview on Therapies in Non-Transfusion-Dependent Thalassemia: Classical to Cutting Edge in Treatment.
The thalassemia issue is a growing worldwide health concern that anticipates the number of patients suffering from the disease will soon increase significantly. Patients with β-thalassemia intermedia (β-TI) manifest mild to intermediate levels of anemia, which is a reason for it to be clinically located between thalassemia minor and β-thalassemia major (β-TM). Notably, the determination of the actual rate of β-TI is more complicated than β-TM. The leading cause of this illness could be partial repression of β-globin protein production; accordingly, the rate of β-globin gene repression is different in patients, and the gene repression intensity creates a different clinical status. This review article provides an overview of functional mechanisms, advantages, and disadvantages of the classic to latest new treatments for this group of patients, depending on the disease severity divided into the typical management strategies for patients with β-TI such as fetal hemoglobin (Hb) induction, splenectomy, bone marrow transplantation (BMT), transfusion therapy, and herbal and chemical iron chelators. Recently, novel erythropoiesis-stimulating agents have been added. Novel strategies are subclassified into molecular and cellular interventions. Genome editing is one of the efficient molecular therapies for improving hemoglobinopathies, especially β-TI. It encompasses high-fidelity DNA repair (HDR), base and prime editing, clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 procedure, nuclease-free strategies, and epigenetic modulation. In cellular interventions, we mentioned the approach pattern to improve erythropoiesis impairments in translational models and patients with β-TI that involve activin II receptor traps, Janus-associated kinase 2 (JAK2) inhibitors, and iron metabolism regulation.
2023-02-01 | Regulation of iron homeostasis by hepatocyte TfR1 requires HFE and contributes to hepcidin suppression in β-thalassemia.
Transferrin receptor 1 (TfR1) performs a critical role in cellular iron uptake. Hepatocyte TfR1 is also proposed to influence systemic iron homeostasis by interacting with the hemochromatosis protein HFE to regulate hepcidin production. Here, we generated hepatocyte Tfrc knockout mice (Tfrcfl/fl;Alb-Cre+), either alone or together with Hfe knockout or β-thalassemia, to investigate the extent to which hepatocyte TfR1 function depends on HFE, whether hepatocyte TfR1 impacts hepcidin regulation by serum iron and erythropoietic signals, and its contribution to hepcidin suppression and iron overload in β-thalassemia. Compared with Tfrcfl/fl;Alb-Cre- controls, Tfrcfl/fl;Alb-Cre+ mice displayed reduced serum and liver iron; mildly reduced hematocrit, mean cell hemoglobin, and mean cell volume; increased erythropoietin and erythroferrone; and unchanged hepcidin levels that were inappropriately high relative to serum iron, liver iron, and erythroferrone levels. However, ablation of hepatocyte Tfrc had no impact on iron phenotype in Hfe knockout mice. Tfrcfl/fl;Alb-Cre+ mice also displayed a greater induction of hepcidin by serum iron compared with Tfrcfl/fl;Alb-Cre- controls. Finally, although acute erythropoietin injection similarly reduced hepcidin in Tfrcfl/fl;Alb-Cre+ and Tfrcfl/fl;Alb-Cre- mice, ablation of hepatocyte Tfrc in a mouse model of β-thalassemia intermedia ameliorated hepcidin deficiency and liver iron loading. Together, our data suggest that the major nonredundant function of hepatocyte TfR1 in iron homeostasis is to interact with HFE to regulate hepcidin. This regulatory pathway is modulated by serum iron and contributes to hepcidin suppression and iron overload in murine β-thalassemia.
other
2026-06-04 | Phase 2a randomized study to evaluate sapablursen in patients with non-transfusion dependent β-thalassemia intermedia.
Non-transfusion-dependent b-thalassemia intermedia (NTDT) is a genetically heterogeneous disorder characterized by decreased β-globin production in erythroid cells resulting from mutations in the β-globin gene that is not treated with transfusion. NTDT is further characterized by a relative excess of a-globin which drives ineffective erythropoiesis resulting in increased iron absorption and ultimately iron overload. Sapablursen is an antisense oligonucleotide (ASO) that reduces the production of transmembrane protease serine 6 (TMPRSS6) and increases hepcidin production. This phase 2a study evaluated the safety, pharmacokinetics, and efficacy of sapablursen in patients with NTDT. Eligible patients had a clinical diagnosis of NTDT with genotypic confirmation of b-globin gene mutations. Twenty-nine patients with NTDT were treated with sapablursen at doses ranging from 30 to 160 mg once every 4 weeks (Q4W) for up to 2 years. Sapablursen was generally safe and well-tolerated. The study did not meet its primary or secondary endpoints of increased blood hemoglobin or reduced liver iron content (LIC). In earlier studies, including a phase 1 trial in healthy volunteers and a phase 2 trial in patients with polycythemia vera, sapablursen produced dose-dependent increases in serum hepcidin levels. However, in patients with non-transfusion-dependent thalassemia (NTDT), similar doses and exposures did not lead to consistent dose-dependent increases in serum hepcidin.. LIC and serum erythroferrone were elevated at baseline and throughout the current study. These two factors may prevent the elevation of serum hepcidin via the TMPRSS6 pathway. The companion article by Zhang et al. explores this mechanism in a mouse model of NTDT. Trial Registration Number: NCT04059406.
2022-11-03 | Case report: Successful outcome of treatment using rituximab in an adult patient with refractory minimal change disease and β-thalassemia complicating autoimmune hemolytic anemia
Minimal change disease (MCD) is one of the common causes of idiopathic nephrotic syndrome (INS), accounting for 10-20% of INS in adults. Glucocorticoids are the most commonly used and effective drugs in the treatment of MCD, but there is still a proportion of adult patients with MCD who are characterized by glucocorticoid resistance, glucocorticoid dependence, and frequent relapse, which are defined as refractory nephrotic syndrome. Glucocorticoid combination with immunosuppressants is frequently used in patients with refractory nephrotic syndrome, and patients concerned about adverse effects caused by long-term high-dose glucocorticoid therapy. Recent studies have suggested that Rituximab (RTX), a chimeric monoclonal antibody targeted against the pan-B-cell marker CD20, combined with a small or medium dose of glucocorticoid has a beneficial effect with less adverse effects on adult patients with refractory MCD. β-thalassemia is an inherited hemoglobulin disorder caused by the mutation of genes that encode β-globin and results in ineffective erythropoiesis. We here report a case of an adult patient with refractory MCD complicated with β-thalassemia minor accompanied by autoimmune hemolytic anemia (AIHA). MCD relapsed several times despite treatment using glucocorticoid combined with or without different immunosuppressive agent regimens. The β-thalassemia minor was caused by heterozygosity for a 4-base deletion mutation [codons 41/42 (-TTCT) BETA0] of the β-globin gene. After the administration of RTX, MCD achieved clinical complete remission, and the anemia due to mild β-thalassemia recovered to normal as well. The disease situation remained stable during 36 months of follow-up. These findings suggest that RTX may contribute to the improvement of refractory MCD and anemia in β-thalassemia minor accompanied by AIHA.
2018-09-12 | Transferrin receptor 2 is a potential novel therapeutic target for β-thalassemia: evidence from a murine model
Abstract β-thalassemias are genetic disorders characterized by anemia, ineffective erythropoiesis, and iron overload. Current treatment of severe cases is based on blood transfusion and iron chelation or allogeneic bone marrow (BM) transplantation. Novel approaches are explored for nontransfusion-dependent patients (thalassemia intermedia) who develop anemia and iron overload. Here, we investigated the erythropoietin (EPO) receptor partner, transferrin receptor 2 (TFR2), as a novel potential therapeutic target. We generated a murine model of thalassemia intermedia specifically lacking BM Tfr2: because their erythroid cells are more susceptible to EPO stimulation, mice show improved erythropoiesis and red blood cell morphology as well as partial correction of anemia and iron overload. The beneficial effects become attenuated over time, possibly due to insufficient iron availability to sustain the enhanced erythropoiesis. Germ line deletion of Tfr2, including haploinsufficiency, had a similar effect in the thalassemic model. Because targeting TFR2 enhances EPO-mediated effects exclusively in cells expressing both receptors, this approach may have advantages over erythropoiesis-stimulating agents in the treatment of other anemias.
2018-03-01 | A contemporary therapeutic approach to bone disease in beta-thalassemia - a review
Homozygous beta-thalassemia represents a serious hemoglobinopathy, in which an amazing prolongation in the survival rate of patients has been achieved over recent decades.A result of this otherwise positive evolution is the fact that bone problems have become a major issue in this group of patients.Through an in-depth review of the related literature, the purpose of this study is to present and comment on the totality of the data that have been published to date pertaining to the prevention and treatment of thalassemia bone-disease, focusing on: the contribution of diet and lifestyle, the treatment of hematologic disease and its complications, the management of hypercalciuria, the role of vitamins and minerals and the implementation of anti-osteoporosis medical regimen.In order to comprehensively gather the above information, we mainly reviewed the international literature through the PubMed database, searching for the preventive and therapeutic data that have been published pertaining to thalassemia bone-disease over the last twenty-nine years.There is no doubt that thalassemia bone-disease is a complication of a multi-factorial etiopathology, which does not follow the rules of classical postmenopausal osteoporosis.Bisphosphonates have been the first line of treatment for many years now, with varied and usually satisfactory results.In addition, over the last few years, more data have arisen for the use of denosumab, teriparatide, and other molecules that are in the clinical trial phase, in beta-thalassemia.
small molecules
2026-09-09 | Safety and Effectiveness of Thalidomide in Transfusion-Dependent and Non-Transfusion-Dependent Thalassaemia Children in Eastern India.
Thalassaemia is a major public health concern in Eastern India, with many children requiring lifelong blood transfusions. Thalidomide, known for its immunomodulatory properties, has shown promise in reducing transfusion needs by increasing fetal hemoglobin production.The safety and efficacy of thalidomide was evaluated in 404 patients aged 2 to 18 years, diagnosed with beta thalassaemia major or intermedia.Mean age was 8.4 years with 54.5 % cases being male. Majority of the patients were Beta thalassaemia major (54.8%). Mean Haemoglobin ± SE at baseline was 6.435 ± 0.092, with a significant increase in haemoglobin levels from 6.435 ± 0.092 at baseline to 8.157 ± 0.069 at the 12 months (p < 0.001). The mean number of transfusions decreased from 1.261 ± 0.051 at 3 months to 1.108 ± 0.074 at 12 months (p < 0.001). The mean spleen size decreased from 3.712 ± 0.087 at baseline to 2.242 ± 0.068 at 12 months (p < 0.001). The mean ferritin level decreased from 1947 ng/mL at baseline to 1554 ng/mL at 12 months (p < 0.001). This decline in ferritin reflects both reduced transfusion requirements and improvement in iron overload. Total bilirubin levels also showed a significant downward trend over 12 months (p < 0.001). At the end of 12 months, 30.7% of the responses were excellent, 52.5% were good, 13.3% were partial and rest 3.5% were no response. Side effects were reported in 62.6% of the patients, out of which most common was constipation (51%).Thalidomide significantly benefits transfusion-dependent thalassaemia patients, with a high proportion showing excellent or good response.
2026-07-22 | Management of nontransfusion dependent thalassemia (NTDT)
Introduction: Nontransfusion dependent Thalassemia (NTDT) like E-beta thalassemia and -thalassemia intermedia are the most common Thalassemia syndrome in India. As compared to transfusion dependent Thalassemia (TDT), Non Transfusion Dependent Thalassemia (NTDT) does not require regular and frequently packed RBC transfusion to prevent anemia related complications. Still NTDT subjects may suffer from the complications of Iron overload due to ineffective erythropoesis and increased intestinal iron absorption. Hydroxyurea therapy which reduces transfusion requirement by raising fetal Hb level and early iron chelation therapy to reduce Liver Iron Concentration (LIC) are mainstay of management in NTDT.Objectives: To study the clinico -hematological profile and management of Non Transfusion Dependent Thalassemia (NTDT)Results: Total 21 children of Non Transfusion Dependent Thalassemia (receiving
2026-02-23 | Pulmonary hypertension in beta thalassemia: a prospective cohort study on treatment outcomes and cardiopulmonary function.
Beta thalassaemia, an inherited blood disorder, exhibits a broad range of phenotypes from asymptomatic to severe anaemia. Pulmonary hypertension (PH) is a major complication in thalassaemia patients, significantly impacting morbidity and mortality. This study aimed to assess the clinical condition of thalassaemia patients with PH over the course of one year while receiving treatment in accordance with the guidelines of the European Society of Cardiology (ESC). A prospective cohort study was carried out at Rohani Hospital in Iran from May 2020 to May 2021. The study included patients diagnosed with beta thalassaemia intermedia who also had PH confirmed by echocardiography. Treatment was administered according to ESC guidelines, incorporating vasodilators and other supportive medications. Clinical and laboratory data were gathered, and statistical analyses were conducted. Nineteen patients, with a mean age of 42.57 ± 8.62 years, participated in the study. Treatment resulted in notable improvements in the 6-minute walk test (6MWT) (p < 0.001), reduced proBNP levels (p = 0.016), and a lower E/e' ratio (p = 0.01), suggesting enhanced right ventricular (RV) function. However, there were no significant changes in pulmonary artery pressure (PAP) or RV size. Additionally, repeated blood transfusions were linked to RV dysfunction. Repeated blood transfusions correlate with RV dysfunction in thalassaemia patients with PH. Vasodilatory treatment improves 6MWT, proBNP levels, and E/e' ratio, indicating RV function enhancement. This study underscores the importance of comprehensive management strategies for thalassaemia patients with PH to mitigate associated complications and improve outcomes.
2025-10-30 | Beta-Thalassemia Intermedia in Disguise: A Case of Delayed Diagnosis in a Child with Persistent Cytopenias
Aplastic anemia and thalassemia are two distinct hematological disorders that are rarely seen in combination. This report describes the case of a 7-year-old boy initially diagnosed with aplastic anemia based on clinical and bone marrow findings, who was later found to have coexistent beta-thalassemia intermedia. The patient presented with chronic pallor, fatigue, gum bleeding, and growth retardation, along with persistent thrombocytopenia since age two. Despite multiple platelet transfusions, steroids, and splenectomy, there was no sustained improvement. Subsequent marrow biopsy confirmed aplastic anemia, and treatment with oxymetholone and cyclosporine was initiated. Persistent anemia led to hemoglobin electrophoresis, revealing elevated HbF (24.3%) and confirming beta-thalassemia intermedia. After treatment with thalidomide and hydroxyurea, his transfusion requirements markedly decreased, with the last transfusion in March 2024. This case underscores the diagnostic complexity of overlapping hematologic disorders, particularly in regions with high thalassemia prevalence. Early utilization of hemoglobin electrophoresis in unexplained or refractory cytopenias can help avoid misdiagnosis and guide timely, effective treatment.
2025-08-07 | Therapeutic Response to Hydroxyurea in Beta-Thalassemia Intermedia with Rare Mutation: A Case Report.
Beta-thalassemia is a hereditary hemoglobinopathy characterized by significant clinical variability, largely influenced by the underlying genetic mutations. We report a 47-year-old female patient with β-thalassemia intermedia harboring a rare homozygous mutation in the β-globin gene promoter: HBB:c.-136C > G (-86 C > G). The patient showed marked clinical response to hydroxyurea therapy with a notable increase in hemoglobin levels, reduction in spleen size and improvement of fatigue and bone pain due to extramedullary hematopoiesis. This report highlights the role of genetic characterization in understanding rare forms of thalassemia and the potential of hydroxyurea as a personalized treatment strategy for patients with unique genetic determinants.
cell therapies
2024-12-31 | Hemolysis due to anti-IH in a patient with beta-thalassemia and Mycoplasma pneumoniae infection.
Anti-IH is a common cold agglutinin that is typically clinically insignificant. We present a case that resulted in hemolysis. A 32-year-old male patient with transfusion-independent beta-thalassemia intermedia presented with symptomatic anemia. His blood sample typed as group B, D+ and demonstrated multiple alloantibodies and cold autoantibodies. He was transfused uneventfully, but re-presented 10 days later with recurrent, worsening anemia. At this time, transfusion of group O, phenotype-matched red blood cells (RBCs) resulted in an acute hemolytic reaction. While anemia was initially attributed to drug-mediated bone marrow toxicit y and subsequently to a delayed hemolytic reaction, further evaluation revealed Mycoplasma pneumoniae infection and a cold agglutinin (anti-IH specificity), indicating a likely autoimmune-mediated anemia due to an infectious etiology. Subsequent transfusion of 2 group B, phenotype-matched RBC units using a blood warmer was uneventful. Anti-IH is only rarely associated with hemolytic transfusion reactions, which may be exacerbated when transfusing group O RBC units to group B patients. M. pneumoniae infection likely led to cold agglutinin-mediated hemolysis of endogenous and transfused RBCs. The patient was successfully managed with intravenous immunoglobulin, steroids, rituximab, erythropoietin, hydroxyurea, and amoxicillin clavulanate/azithromycin. This case illustrates the importance of infectious disease evaluation in patients with unexplained anemia, the potential clinical significance of autoanti-IH, and the value of providing type-specific RBC units in these circumstances.
2024-10-01 | Integrated metabolomic and microbiome analysis identifies Cupriavidus metallidurans as a potential therapeutic target for β-thalassemia.
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.
2021-03-16 | Longitudinal follow-up of patients with thalassaemia intermedia who started transfusion therapy in adulthood: a cohort study.
We longitudinally evaluated the effects of regular blood transfusions (BTs), in the real-life context of the Myocardial Iron Overload in Thalassaemia network, in patients with thalassaemia intermedia (TI). We considered 88 patients with TI (52 females) who started regular BTs after the age of 18 years. Magnetic resonance imaging was used to quantify iron overload and biventricular function. For 56·8% of the patients there were more than two indications for the transition to regular BTs, with anaemia present in 94·0% of the cases. A significant decrease in nucleated red blood cells, platelets, lactate dehydrogenase, bilirubin, and uric acid levels was detected 6 months after starting regular BTs. After the transition to the regular BT regimen there was a significant increase only in the frequency of hypothyroidism and osteopenia, and a significant decrease in liver iron and cardiac index. The percentage of chelated patients increased significantly after starting regular BTs. The decision to regularly transfuse patients with TI may represent a way to prevent or slow down the natural progression of the disease, despite the more complex initial management.
2021-03-01 | Red Blood Cell Exchange in a Patient With Extramedullary Hematopoiesis and Cor Pulmonale Secondary to Beta Thalassemia
Rationale: Beta thalassemia is a congenital defect in the production of the beta globin chain. Patients with beta thalassemia major will have higher levels of hemoglobin F (HbF), which is suboptimal in releasing oxygen to tissue. Herein, we describe the use of red blood cell (RBC) exchange transfusion, a therapy typically used in sickle cell patients, in the management of a patient with beta thalassemia with extensive extramedullary hematopoiesis and elevated levels of HbF. Patient concerns: A 34-year-old male of mixed African American and Southeast Asian descent with a known history of beta thalassemia major presented with progressive dyspnea on exertion with marked fatigue. Diagnoses: The patient was transferred to our facility for management of acute hypoxemic, hypercapnic respiratory failure associated with cor pulmonale. Interventions: The patient was initially managed with non-invasive positive pressure support ventilation (NIPPV) and intravenous diuresis. Hydroxyurea and epoprostenol nebulization were added to his treatment regimen; however, he progressively became more unstable, necessitating inotropic support. With extramedullary hematopoiesis leading to mass-like effect on critical organs and very high HbF (96%) thought to contribute to his presentation, red blood cell exchange transfusion was initiated once the blood pressure stabilized. Outcomes: The patient clinically improved, and was discharged home within a week on supplemental oxygen by nasal cannula and long-term red blood cell exchange. Lessons: We postulated that significantly elevated HbF contributed to the patient’s chronic hypoxia and subsequent respiratory complications. Based on the patient's clinical improvement following the intervention, we believe that RBC exchange transfusion could be considered in the management of beta thalassemia patients with significantly elevated levels of HbF.
2019-01-01 | Red blood cell alloimmunisation in transfusion-dependent thalassaemia: a systematic review.
Chronic red blood cell transfusion is the first-line treatment for severe forms of thalassaemia. This therapy is, however, hampered by a number of adverse effects, including red blood cell alloimmunisation. The aim of this systematic review was to collect the current literature data on erythrocyte alloimmunisation.We performed a systematic search of the literature which identified 41 cohort studies involving 9,256 patients.The prevalence of erythrocyte alloimmunisation was 11.4% (95% CI: 9.3-13.9%) with a higher rate of alloimmunisation against antigens of the Rh (52.4%) and Kell (25.6%) systems. Overall, alloantibodies against antigens belonging to the Rh and Kell systems accounted for 78% of the cases. A higher prevalence of red blood cell alloimmunisation was found in patients with thalassaemia intermedia compared to that among patients with thalassaemia major (15.5 vs 12.8%).Matching transfusion-dependent thalassaemia patients and red blood cell units for Rh and Kell antigens should be able to reduce the risk of red blood cell alloimmunisation by about 80%.
proteins
2025-10-20 | Expression of the FAM132B Gene in Iranian Patients with Beta-Thalassemia
Background: Iron homeostasis is a complex process involving multiple factors. Erythroblasts secrete erythroferrone (ERFE), which affects hepcidin production, thereby enhancing iron uptake. This study aimed to investigate the expression of the ERFE-encoding FAM132B gene in Iranian patients with beta-thalassemia major (BTM) and beta-thalassemia intermedia (BTI). Materials and Methods: A total of 40 BTM and BTI patients and 20 healthy blood donors as a control group were recruited. Total RNA was extracted from whole blood samples, and cDNA was synthesized. Gene expression was quantified using a SYBR Green-based real-time PCR (RT-PCR) assay. Data analysis was performed by the GraphPad Prism program using the one-way ANOVA test. Results: The expression of the FAM132B gene was upregulated in BTI patients compared to BTM patients (p = 0.0151). Despite the higher mRNA fold change in BTI patients, no significant difference was observed in the FAM132B gene expression between beta-thalassemia patients (major and intermedia) and the control group. Conclusion: The expression of the FAM132B gene was different between beta-thalassemia major and intermedia patients. Further studies should be conducted to better elucidate the role of erythroferrone as a potential therapeutic target in patients with beta-thalassemia.
2024-02-08 | Beta-Thalassemia: A Pharmacological Drug-Based Treatment
This review was performed to determine the potential of drugs that can remove or decrease the requirements for blood transfusion among beta (β)-thalassemia patients. A comprehensive literature search was conducted to identify clinical trials and studies using PubMed Central, Google Scholar, PubMed, and ScienceDirect archived articles published from 1996 to November 2023. According to this review, clinical trials for a number of drugs, including luspatercept, sotatercept, mitapivat, etavopivat, hydroxyurea, rapamycin, decitabine, thalidomide, and quercetin, have been performed as part of efforts to improve the cure strategy for β-thalassemia. Of these drugs, luspatercept and sotatercept have exhibited particularly promising results and have been granted US Food and Drug Administration (FDA) approval for use in β-thalassemia patients. The mode of action for the drugs luspatercept and sotatercept involves the stimulation of hemoglobin (Hb) production or enhancement of its functionality, thereby decreasing reliance on blood transfusions and enhancing the overall quality of life. In this way, drugs like luspatercept and sotatercept present an opportunity to notably decrease the necessity for blood transfusions in β-thalassemia patients, improving their standard of living and overall prognosis. However, more research is needed to evaluate the effectiveness and safety of these drugs in the long run.
2024-02-06 | BMI1 regulates human erythroid self-renewal through both gene repression and gene activation
Abstract The limited proliferative capacity of erythroid precursors is a major obstacle to generate sufficient numbers of in vitro-derived red blood cells (RBC) for clinical purposes. We and others have determined that BMI1, a member of the polycomb repressive complex 1 (PRC1), is both necessary and sufficient to drive extensive proliferation of self-renewing erythroblasts (SREs). However, the mechanisms of BMI1 action remain poorly understood. BMI1 overexpression led to 10 billion-fold increase BMI1-induced (i)SRE self-renewal. Despite prolonged culture and BMI1 overexpression, human iSREs can terminally mature and agglutinate with typing reagent monoclonal antibodies against conventional RBC antigens. BMI1 and RING1B occupancy, along with repressive histone marks, were identified at known BMI1 target genes, including the INK-ARF locus, consistent with an altered cell cycle following BMI1 inhibition. We also identified upregulated BMI1 target genes with low repressive histone modifications, including key regulator of cholesterol homeostasis. Functional studies suggest that both cholesterol import and synthesis are essential for BMI1-associated self-renewal. These findings support the hypothesis that BMI1 regulates erythroid self-renewal not only through gene repression but also through gene activation and offer a strategy to expand the pool of immature erythroid precursors for eventual clinical uses.
2019-01-08 | Luspatercept improves hemoglobin levels and blood transfusion requirements in a study of patients with β-thalassemia
Abstract β-thalassemia is a hereditary disorder with limited approved treatment options; patients experience anemia and its complications, including iron overload. The study aim was to determine whether luspatercept could improve anemia and disease complications in patients with β-thalassemia. This open-label, nonrandomized, uncontrolled study consisted of a 24-week dose-finding and expansion stage (initial stage) and a 5-year extension stage, currently ongoing. Sixty-four patients were enrolled; 33 were non–transfusion dependent (mean hemoglobin, <10.0 g/dL; <4 red blood cell [RBC] units transfused per 8 weeks), and 31 were transfusion dependent (≥4 RBC units per 8 weeks). Patients received 0.2 to 1.25 mg/kg luspatercept subcutaneously every 21 days for ≥5 cycles (dose-finding stage) and 0.8 to 1.25 mg/kg (expansion cohort and 5-year extension). The primary end point was erythroid response, defined as hemoglobin increase of ≥1.5 g/dL from baseline for ≥14 consecutive days (without RBC transfusions) for non–transfusion-dependent patients or RBC transfusion burden reduction ≥20% over a 12-week period vs the 12 weeks before treatment for transfusion-dependent patients. Eighteen non–transfusion-dependent patients (58%) receiving higher dose levels of luspatercept (0.6-1.25 mg/kg) achieved mean hemoglobin increase ≥1.5 g/dL over ≥14 days vs baseline. Twenty-six (81%) transfusion-dependent patients achieved ≥20% reduction in RBC transfusion burden. The most common grade 1 to 2 adverse events were bone pain, headache, and myalgia. As of the cutoff, 33 patients remain on study. In this study, a high percentage of β-thalassemia patients receiving luspatercept had hemoglobin or transfusion burden improvements. These findings support a randomized clinical trial to assess efficacy and safety. This study was registered at www.clinicaltrials.gov as #NCT01749540 and #NCT02268409.
2019-01-04 | A computational model to understand mouse iron physiology and disease
It is well known that iron is an essential element for life but is toxic when in excess or in certain forms. Accordingly there are many diseases that result directly from either lack or excess of iron. Yet many molecular and physiological aspects of iron regulation have only been discovered recently and others are still elusive. There is still no good quantitative and dynamic description of iron absorption, distribution, storage and mobilization that agrees with the wide array of phenotypes presented in several iron-related diseases. The present work addresses this issue by developing a mathematical model of iron distribution in mice calibrated with ferrokinetic data and subsequently validated against data from mouse models of iron disorders, such as hemochromatosis, β-thalassemia, atransferrinemia and anemia of inflammation. To adequately fit the ferrokinetic data required inclusion of the following mechanisms: a) transferrin-mediated iron delivery to tissues, b) induction of hepcidin by transferrin-bound iron, c) ferroportin-dependent iron export regulated by hepcidin, d) erythropoietin regulation of erythropoiesis, and e) liver uptake of NTBI. The utility of the model to simulate disease interventions was demonstrated by using it to investigate the outcome of different schedules of transferrin treatment in β-thalassemia.
gene therapies
2026-02-27 | Systematic Review of Non-Coding Genomic Variants in Globin and Non-Globin Clusters and Their Impact on Phenotypic Severity in Thalassemia and Sickle Cell Disease.
Background: Haemoglobinopathies such as beta-thalassemia (β-thal), alpha-thalassemia (α-thal) and sickle cell disease (SCD) are characterised by pathogenic gene variations (mutations) in the globin genes. Patients with haemoglobinopathies have the same disease-causing coding variations with very different disease phenotypes, from requiring blood transfusions to being non-symptomatic. The gap between the expected clinical outcomes based on primary coding mutations (the genotype) and the actual observed symptoms (the phenotype) often remains unexplained. We refer to the contribution of secondary genetic modifiers-specifically, non-coding variants of the genome that alter globin gene expression and pathophysiology-as the "missing heritability" of the clinical presentation [Primary Mutation + Missing Heritability (Non-Coding Variants) = Actual Clinical Phenotype]. Objectives: This systematic review aims to find evidence connecting genetic differences outside of the protein-coding region, as in promoters, enhancers or untranslated regions (UTRs), to the clinical severity (phenotype) of beta-thalassemia, alpha-thalassaemia and SCD. We summarise the molecular basis of phenotypic variation among haemoglobinopathy patients with identical variations to reveal their missing heritability and to enhance our understanding of prognostic strategies. Methods: This systematic review was performed in accordance with the PRISMA 2020 guidelines. We used search terms related to haemoglobinopathies, non-coding variation, SNP, promoters, enhancers and clinical severity to search major databases (PubMed and Google Scholar) as of October 2025. A total of 527 (out of 572) abstracts were fit for initial screening to identify the eligible reports. Due to heterogeneity in study designs and reported outcomes, findings were synthesised descriptively and grouped by variant mechanism (cis-acting and trans-acting). The final analysis included 89 articles that demonstrated a direct association between a non-coding genomic variant and a quantitative measure of clinical severity. Results: Two main groups of non-coding variants (NCVs) that modulate foetal haemoglobin (HbF) induction were identified. The first major group comprises cis-acting variants within globin gene clusters (HBG2 promoter XmnI polymorphism, HBB promoter mutations and α-globin enhancer variants), while the second major group comprises trans-acting quantitative trait loci (QTLs) (BCL11A and HBS1L-MYB loci). Non-globin NCVs in the UGT1A1 promoter were also found to influence the severity measures in β-thal and SCD. NCVs primarily alter the binding of transcription factors and the looping dynamics of chromatin, modulating the α/β chain balance ratio and γ-globin repression. The XmnI polymorphism is the most prominent cis-acting modifier associated with β-thal intermedia. The promoter polymorphisms in TNF-α and VCAM1 are associated with vascular complications in SCD. Conclusions: NCVs are fundamental when determining the clinical measures of haemoglobinopathies, in addition to coding variants. NCV screening should be integrated for clinical prognosis for the accurate prediction of haemoglobinopathy severity and associated high-risk complications. NCVs may represent promising targets for next-generation gene editing and therapeutic intervention strategies aimed at modifying the severity of β-thal, α-thal and SCD.
2025-03-31 | Treatment Options for Beta-Thalassemia
Beta-thalassemia, a hereditary blood disorder caused by point mutations affecting beta-globin synthesis, impairs erythrocyte oxygen transport. Due to its resistance, beta-thalassemia originally propagated in regions with high malaria prevalence. More recently, it has spread globally through human migration, impacting millions. Early screening of beta-thalassemia can be preconception, fetal, and infant testing and is vital for diagnosis and treatment plans. The types major, minor, and intermedia are classified based on their respective mutations and result in various symptoms ranging in severity. Regular erythrocyte transfusions replace faulty blood cells to treat thalassemia major. These transfusions cause iron overload, a severe side effect that is often treated with chelation therapy. Currently, the only cure for beta-thalassemia is hematopoietic stem cell transplantation. Hematopoietic stem cells are undifferentiated cells in the red bone marrow that proliferate and differentiate into various blood cells, including erythrocytes. Transplantation replaces deleterious hematopoietic stem cells with healthy ones that can differentiate into erythrocytes with full oxygen-carrying capacity. While an effective cure, there are many challenges pre-transplantation and post-transplantation; for example, finding suitable donors and preventing complications. Through medical advances in stem cell exploration and gene editing techniques, research continues to progress and discover potential cures. CRISPR-Cas, a prominent gene editing tool, has found success in identifying and modifying specific gene sequences. Researchers hope to apply CRISPR-Cas to the beta-globin synthesis gene and prevent beta-thalassemia. As technology advances, the practical and ethical challenges of accessibility, cost, and safety persist at the forefront of patient care.
2023-09-20 | Global Trends on β-thalassemia Research over 10 Years: A Bibliometric Analysis
Abstract Introduction Thalassemia, an inherited quantitative globin disorder, is the most prevalent monogenic disease globally. While severe alpha thalassemia results in intrauterine death, β-thalassemia manifests during childhood due to the "second conversion of hemoglobin," garnering increased attention in recent decades. Methods In this study, a bibliometric analysis will be conducted of thalassemia articles published in the Web of Science Core Collection database between 2013 and 2023 to establish a comprehensive overview and to identify emerging trends. A total of 5655 studies published between 2013 and 2023 were systematically retrieved, and annual publications demonstrated a steady increase, maintaining a high level over the past decade. Results The United States contributed the highest number of publications, followed by China. Notably, the journal Blood emerged as the leading authority in β-thalassemia research. Analysis of research hotspots revealed that the pathogenesis of β-thalassemia is primarily linked to iron overload, anemia, gene mutations, and ineffective erythropoiesis. Furthermore, recent studies focusing on gene editing therapies present promising avenues for future investigation. Conclusion These findings grasp the research status of β-thalassemia and shed new light on future research frontiers.
2023-06-28 | An Expert Overview on Therapies in Non-Transfusion-Dependent Thalassemia: Classical to Cutting Edge in Treatment.
The thalassemia issue is a growing worldwide health concern that anticipates the number of patients suffering from the disease will soon increase significantly. Patients with β-thalassemia intermedia (β-TI) manifest mild to intermediate levels of anemia, which is a reason for it to be clinically located between thalassemia minor and β-thalassemia major (β-TM). Notably, the determination of the actual rate of β-TI is more complicated than β-TM. The leading cause of this illness could be partial repression of β-globin protein production; accordingly, the rate of β-globin gene repression is different in patients, and the gene repression intensity creates a different clinical status. This review article provides an overview of functional mechanisms, advantages, and disadvantages of the classic to latest new treatments for this group of patients, depending on the disease severity divided into the typical management strategies for patients with β-TI such as fetal hemoglobin (Hb) induction, splenectomy, bone marrow transplantation (BMT), transfusion therapy, and herbal and chemical iron chelators. Recently, novel erythropoiesis-stimulating agents have been added. Novel strategies are subclassified into molecular and cellular interventions. Genome editing is one of the efficient molecular therapies for improving hemoglobinopathies, especially β-TI. It encompasses high-fidelity DNA repair (HDR), base and prime editing, clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 procedure, nuclease-free strategies, and epigenetic modulation. In cellular interventions, we mentioned the approach pattern to improve erythropoiesis impairments in translational models and patients with β-TI that involve activin II receptor traps, Janus-associated kinase 2 (JAK2) inhibitors, and iron metabolism regulation.
2023-02-01 | Regulation of iron homeostasis by hepatocyte TfR1 requires HFE and contributes to hepcidin suppression in β-thalassemia.
Transferrin receptor 1 (TfR1) performs a critical role in cellular iron uptake. Hepatocyte TfR1 is also proposed to influence systemic iron homeostasis by interacting with the hemochromatosis protein HFE to regulate hepcidin production. Here, we generated hepatocyte Tfrc knockout mice (Tfrcfl/fl;Alb-Cre+), either alone or together with Hfe knockout or β-thalassemia, to investigate the extent to which hepatocyte TfR1 function depends on HFE, whether hepatocyte TfR1 impacts hepcidin regulation by serum iron and erythropoietic signals, and its contribution to hepcidin suppression and iron overload in β-thalassemia. Compared with Tfrcfl/fl;Alb-Cre- controls, Tfrcfl/fl;Alb-Cre+ mice displayed reduced serum and liver iron; mildly reduced hematocrit, mean cell hemoglobin, and mean cell volume; increased erythropoietin and erythroferrone; and unchanged hepcidin levels that were inappropriately high relative to serum iron, liver iron, and erythroferrone levels. However, ablation of hepatocyte Tfrc had no impact on iron phenotype in Hfe knockout mice. Tfrcfl/fl;Alb-Cre+ mice also displayed a greater induction of hepcidin by serum iron compared with Tfrcfl/fl;Alb-Cre- controls. Finally, although acute erythropoietin injection similarly reduced hepcidin in Tfrcfl/fl;Alb-Cre+ and Tfrcfl/fl;Alb-Cre- mice, ablation of hepatocyte Tfrc in a mouse model of β-thalassemia intermedia ameliorated hepcidin deficiency and liver iron loading. Together, our data suggest that the major nonredundant function of hepatocyte TfR1 in iron homeostasis is to interact with HFE to regulate hepcidin. This regulatory pathway is modulated by serum iron and contributes to hepcidin suppression and iron overload in murine β-thalassemia.
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2026-06-04 | Phase 2a randomized study to evaluate sapablursen in patients with non-transfusion dependent β-thalassemia intermedia.
Non-transfusion-dependent b-thalassemia intermedia (NTDT) is a genetically heterogeneous disorder characterized by decreased β-globin production in erythroid cells resulting from mutations in the β-globin gene that is not treated with transfusion. NTDT is further characterized by a relative excess of a-globin which drives ineffective erythropoiesis resulting in increased iron absorption and ultimately iron overload. Sapablursen is an antisense oligonucleotide (ASO) that reduces the production of transmembrane protease serine 6 (TMPRSS6) and increases hepcidin production. This phase 2a study evaluated the safety, pharmacokinetics, and efficacy of sapablursen in patients with NTDT. Eligible patients had a clinical diagnosis of NTDT with genotypic confirmation of b-globin gene mutations. Twenty-nine patients with NTDT were treated with sapablursen at doses ranging from 30 to 160 mg once every 4 weeks (Q4W) for up to 2 years. Sapablursen was generally safe and well-tolerated. The study did not meet its primary or secondary endpoints of increased blood hemoglobin or reduced liver iron content (LIC). In earlier studies, including a phase 1 trial in healthy volunteers and a phase 2 trial in patients with polycythemia vera, sapablursen produced dose-dependent increases in serum hepcidin levels. However, in patients with non-transfusion-dependent thalassemia (NTDT), similar doses and exposures did not lead to consistent dose-dependent increases in serum hepcidin.. LIC and serum erythroferrone were elevated at baseline and throughout the current study. These two factors may prevent the elevation of serum hepcidin via the TMPRSS6 pathway. The companion article by Zhang et al. explores this mechanism in a mouse model of NTDT. Trial Registration Number: NCT04059406.
2022-11-03 | Case report: Successful outcome of treatment using rituximab in an adult patient with refractory minimal change disease and β-thalassemia complicating autoimmune hemolytic anemia
Minimal change disease (MCD) is one of the common causes of idiopathic nephrotic syndrome (INS), accounting for 10-20% of INS in adults. Glucocorticoids are the most commonly used and effective drugs in the treatment of MCD, but there is still a proportion of adult patients with MCD who are characterized by glucocorticoid resistance, glucocorticoid dependence, and frequent relapse, which are defined as refractory nephrotic syndrome. Glucocorticoid combination with immunosuppressants is frequently used in patients with refractory nephrotic syndrome, and patients concerned about adverse effects caused by long-term high-dose glucocorticoid therapy. Recent studies have suggested that Rituximab (RTX), a chimeric monoclonal antibody targeted against the pan-B-cell marker CD20, combined with a small or medium dose of glucocorticoid has a beneficial effect with less adverse effects on adult patients with refractory MCD. β-thalassemia is an inherited hemoglobulin disorder caused by the mutation of genes that encode β-globin and results in ineffective erythropoiesis. We here report a case of an adult patient with refractory MCD complicated with β-thalassemia minor accompanied by autoimmune hemolytic anemia (AIHA). MCD relapsed several times despite treatment using glucocorticoid combined with or without different immunosuppressive agent regimens. The β-thalassemia minor was caused by heterozygosity for a 4-base deletion mutation [codons 41/42 (-TTCT) BETA0] of the β-globin gene. After the administration of RTX, MCD achieved clinical complete remission, and the anemia due to mild β-thalassemia recovered to normal as well. The disease situation remained stable during 36 months of follow-up. These findings suggest that RTX may contribute to the improvement of refractory MCD and anemia in β-thalassemia minor accompanied by AIHA.
2018-09-12 | Transferrin receptor 2 is a potential novel therapeutic target for β-thalassemia: evidence from a murine model
Abstract β-thalassemias are genetic disorders characterized by anemia, ineffective erythropoiesis, and iron overload. Current treatment of severe cases is based on blood transfusion and iron chelation or allogeneic bone marrow (BM) transplantation. Novel approaches are explored for nontransfusion-dependent patients (thalassemia intermedia) who develop anemia and iron overload. Here, we investigated the erythropoietin (EPO) receptor partner, transferrin receptor 2 (TFR2), as a novel potential therapeutic target. We generated a murine model of thalassemia intermedia specifically lacking BM Tfr2: because their erythroid cells are more susceptible to EPO stimulation, mice show improved erythropoiesis and red blood cell morphology as well as partial correction of anemia and iron overload. The beneficial effects become attenuated over time, possibly due to insufficient iron availability to sustain the enhanced erythropoiesis. Germ line deletion of Tfr2, including haploinsufficiency, had a similar effect in the thalassemic model. Because targeting TFR2 enhances EPO-mediated effects exclusively in cells expressing both receptors, this approach may have advantages over erythropoiesis-stimulating agents in the treatment of other anemias.
2018-03-01 | A contemporary therapeutic approach to bone disease in beta-thalassemia - a review
Homozygous beta-thalassemia represents a serious hemoglobinopathy, in which an amazing prolongation in the survival rate of patients has been achieved over recent decades.A result of this otherwise positive evolution is the fact that bone problems have become a major issue in this group of patients.Through an in-depth review of the related literature, the purpose of this study is to present and comment on the totality of the data that have been published to date pertaining to the prevention and treatment of thalassemia bone-disease, focusing on: the contribution of diet and lifestyle, the treatment of hematologic disease and its complications, the management of hypercalciuria, the role of vitamins and minerals and the implementation of anti-osteoporosis medical regimen.In order to comprehensively gather the above information, we mainly reviewed the international literature through the PubMed database, searching for the preventive and therapeutic data that have been published pertaining to thalassemia bone-disease over the last twenty-nine years.There is no doubt that thalassemia bone-disease is a complication of a multi-factorial etiopathology, which does not follow the rules of classical postmenopausal osteoporosis.Bisphosphonates have been the first line of treatment for many years now, with varied and usually satisfactory results.In addition, over the last few years, more data have arisen for the use of denosumab, teriparatide, and other molecules that are in the clinical trial phase, in beta-thalassemia.
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Drug Discovery Landscape
7 orphan drug designations for Beta-thalassemia intermedia, including 1 approved therapy.
7 orphan drug designations for Beta-thalassemia intermedia, including 1 approved therapy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Synthetic 2′-O-(2-methoxyethyl)-modified antisense oligonucleotide linked to a triantennary cluster of N-acetyl galactosamine sugars targeting transmembrane protease, serine 6 mRNA | oligonucleotides | EMA | Ionis Development (Ireland) Limited | |
Rusfertide acetate | peptides | EMA | [INACTIVE] IQVIA RDS Ireland Limited | |
N-carboxymethyl-glycyl-L-threonyl-L-histidyl-L-3,3-diphenylalanyl-L-piperidincarboxy-3-yl-L-arginyl-L-S-methylthio-cystyl-L-arginyl-L-tryptophyl-aminohexanyl-N-carboxamidomethyl-glycine N-hexadecylamide [M012] | — | EMA | — | QRC Consultants Limited |
Hepcidin [LJPC-401] | peptides | EMA | La Jolla Pharmaceutical II B.V. | |
sotatercept | antibodies | FDA | Celgene Corporation | |
Betibeglogene autotemcel [Zynteglo] | gene therapies | EMA | bluebird bio (Netherlands) B.V. | |
deferiprone [Ferriprox] | small molecules | FDA | Approved | Chiesi USA, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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