RARE DISEASE
Beta-thalassemia
Beta-thalassemia
Beta-thalassemia
Drug discovery
29
drugs
With orphan designations
Overview
Beta-thalassemia is an inherited hemoglobinopathy caused by HBB gene mutations, leading to reduced or absent β-globin synthesis. This results in ineffective erythropoiesis, hemolytic anemia, and complications including iron overload, skeletal abnormalities, and multi-organ damage. It manifests as transfusion-dependent thalassemia (TDT) or non-transfusion-dependent thalassemia (NTDT), with severity ranging from asymptomatic carriers to life-threatening anemia [1][5][6].
Burden
Clinical: Iron overload cardiomyopathy remains the leading cause of mortality; endocrine dysfunction, osteoporosis, and hepatosplenomegaly common [10][15].
Economic: Lifetime costs exceed $10M per TDT patient due to transfusions, monitoring, and complications [2][9].
Psychosocial: Chronic treatment needs impair quality of life, particularly in regions with limited healthcare access [9][19][20].
Therapies
Transfusion support: Regular RBC transfusions for TDT, paired with iron chelation (deferasirox, deferiprone) [5][16].
Curative options: Allogeneic stem cell transplant (limited by donor availability) and gene therapy (e.g., betibeglogene autotemcel, CASGEVY™) [8][13][18].
Emerging therapies: Luspatercept (enhances erythropoiesis), thalidomide (induces HbF), and novel agents targeting iron metabolism (e.g., etavopivat) [3][10][12].
Categories: rare endocrine diseases, rare genetic diseases, rare hematological diseases, rare renal diseases, rare transplant-related disorders
Research Papers
3,104 drug discovery papers about Beta-thalassemia, with 1 first-in-class and 14 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
3,104 drug discovery papers about Beta-thalassemia, with 1 first-in-class and 14 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-01 | Structure-guided targeting of the GATAD2A-CHD4 interaction within the MBD2-NuRD complex results in high levels of HbF in adult erythroid cells.
Fetal hemoglobin (HbF) expression is silenced postnatally in adult erythroid cells. Sufficiently increased expression of HbF has been shown to overcome the pathophysiologic sequelae of both sickle cell disease and beta-thalassemia. As the MBD2a-NuRD chromatin remodeling complex is required for silencing of HbF, the present studies were aimed at exploring a potential therapeutic approach for disrupting this complex. AlphaFold 3 and a recent crystal structure were employed to predict the critical interaction domains linking GATAD2A in the histone deacetylase core subcomplex (HDCC) of NuRD and the CHD4 ATPase which has been shown to be required for silencing of the fetal gamma-globin ( HBG ) genes. The two predicted critical domains, the CR2 helical domain of GATAD2A and the C-terminal domains 1 and 2 (C1b and C2ab) of CHD4, were validated by in vitro biophysical studies. Mutation of two amino acids in the CR2 helical domain of the endogenous GATAD2A gene in HUDEP-2 cells resulted in dissociation of CHD4, loss of repressive chromatin over the HBG promoter and ~40% HbF levels compared to < 1% in control cells. Strikingly, enforced expression of a peptide containing the helical portion of the CR2 domain of GATAD2A in both HUDEP-2 cells and primary adult erythroid cells resulted in high levels of HbF, with up to ~75% HbF compared to mutant peptide control level of ~9% in the latter without perturbing erythroid differentiation. These results suggest that targeting the critical interaction domains of GATAD2A and CHD4 with a macrocyclic peptide or small molecule may lead to much needed small molecule therapeutics for sickle cell disease. Association of CHD4 with the HDCC core of the MBD2-NuRD chromatin remodeling complex is required for silencing of HbF expression in adult human erythroid cellsGenetic alteration or enforced peptide expression of a critical helical domain of GATAD2A results in dissociation of CHD4 from the MBD2-NuRD complex and high-level expression of HbF.
2026-07-23 | Fludarabine, Busulfan, Thiotepa, and Melphalan: A Novel Low-Toxicity Myeloablative Conditioning Regimen for Haploidentical HSCT in Children and Adolescents Aged ≥7 Years With Transfusion-Dependent β-Thalassemia.
Graft failure and transplant-related mortality remain major barriers to haploidentical donor hematopoietic stem cell transplantation (HID-HSCT) in children and adolescents aged ≥7 years with transfusion-dependent thalassemia (TDT). Thus, a novel low-toxicity myeloablative conditioning regimen was developed to improve transplantation outcomes. In this prospective, single-center study (clinical trial registration ChiCTR2300071890), TDT patients aged ≥7 years were enrolled to evaluate the safety and efficacy of a conditioning regimen comprising fludarabine, busulfan, thiotepa, and melphalan (F-BMT). For HID recipients, graft-versus-host disease (GVHD) prophylaxis included half-dose PTCY combined with the in vivo T-cell depletion (porcine anti-human lymphocyte immunoglobulin or rabbit anti-human thymocyte globulin), along with other immunosuppressive agents. The primary endpoint was the 2-year thalassemia-free survival (TFS) rate. From June 2023 to August 2024, 29 TDT patients aged ≥7 years undergoing HID-HSCT were enrolled (14 males, 15 females). The 2-year TFS and overall survival rates were both 93.1%. Neutrophil and platelet engraftment were achieved in all patients, with no reported graft failure. The observed incidence of Grade II-IV acute GVHD was 17.2%. Chronic GVHD occurred in 6.9% of the patients. Regimen-related toxicities were manageable, with only one case of sinusoidal obstruction syndrome and three cases of hemorrhagic cystitis, all of which resolved with supportive treatment. No mixed chimerism was observed. The F-BMT regimen provides effective myeloablation with reduced toxicity, supporting its feasibility for HID-HSCT in TDT patients aged ≥7 years.
2026-07-08 | Unlocking thalidomide response as a hemoglobin F augmentation agent in transfusion-dependent β-thalassemia: the genetic impact of BCL11A, HBS1L-MYB, and XmnI polymorphism.
Thalidomide has been found to augment fetal hemoglobin (HbF) synthesis, thereby decreasing transfusion requirements in patients with β-thalassemia. Elevated fetal hemoglobin, influenced by genetic polymorphisms, can significantly modify the clinical severity of β-thalassemia. The study aimed to determine the frequency of the XmnI (rs7482144), BCL11A (rs766432), and HBS1L-MYB (rs9399137) polymorphisms in patients with β-thalassemia and to evaluate their association with the response to thalidomide therapy. This prospective observational study was conducted at Baqai Medical university. One hundred transfusion-dependent β-thalassemia patients on low-dose thalidomide (2 mg/kg/day) were enrolled from Muhammadi blood bank and diagnostics center, Karachi. The outcome measures of response were defined as an increase in hemoglobin (Hb) levels and reduction in blood transfusion frequency following three months of thalidomide treatment, based on which participants were classified as excellent responders, good responders, or non-responders. The Xmn1 (rs7482144), BCL11A (rs766432) and HBS1L-MYB (rs9399137) single nucleotide polymorphisms (SNPs) were detected using the Amplification Refractory Mutation System Polymerase chain reaction (ARMS-PCR). Among the 100 patients, the rs7482144 was present in 68% of cases, rs766432 in 47%, and rs9399137 in 20%. Following three months of thalidomide treatment, Hb levels (9.3 ± 1.5 g/dl) increased significantly compared to baseline levels (5.4 ± 1.6 g/dl) (p<.001). An overall response rate of 87% was recorded. Results showed that minor allele-containing genotypes of three SNPs were significantly associated with an increased likelihood of excellent response [rs7482144: p=.001, RR:1.733; rs766432: p<.001, RR:3.070; rs9399137: p=.023, RR:4.043]. Post-treatment HbF increment was correlated with the cumulative number of minor alleles across the three significant SNPs among excellent responders, with HbF being lower in individuals having ≤ 1 polymorphism (74.0%±19.2%) compared with those carrying 2 (83.0%±8.6%; p=.033) or 3 polymorphisms (97.3%±0.5%; p=.01). Our study indicates that SNPs within HBG2(rs7482144), BCL11A(rs766432), and HBS1L-MYB (rs9399137) region are strongly associated with thalidomide responsiveness in β-thalassemia patients, with the overall number of minor alleles serving as a potential marker for therapeutic response.
2026-07-04 | Low- to moderate-dose thalidomide combination rescue after luspatercept failure in transfusion-dependent β-thalassemia: a real-world cohort study.
A proportion of transfusion-dependent β-thalassemia (TDT) patients show suboptimal or heterogeneous response to luspatercept. We explored a structured rescue approach by adding low- to moderate-dose thalidomide after predefined luspatercept failure in real-world practice. This study was a single-center retrospective cohort study. Adults with TDT on luspatercept who met predefined criteria for suboptimal response (failure to achieve ≥ 33% reduction in RBC units over a 12-week window versus each patient's baseline 12-week window, or failure to increase Hb by ≥ 1.0 g/dL under an unchanged transfusion trigger) received thalidomide 25-50 mg once daily while continuing luspatercept. Primary endpoint was 12-week transfusion independence (TI), defined as no transfusion for 12 consecutive weeks and Hb ≥ 9.0 g/dL. Secondary endpoints included ≥ 33%/≥50% reductions in RBC units over matched 12-week windows, longitudinal Hb change, and safety graded by CTCAE v5.0 and reported as exposure-adjusted incidence rates. Eleven patients were included (median age 23 years; female 45.5%; β⁰/β⁰ 18.2%; prior splenectomy 63.6%). Twelve-week transfusion independence (TI) was achieved in 4/11 patients (36.4%; 95% CI 15.2-64.6). Proportions with ≥ 33% and ≥ 50% reductions in RBC units over matched 12-week windows were 45.5% (95% CI 21.3-72.0) and 45.5% (95% CI 21.3-72.0), respectively. Hemoglobin increased by 4.0 g/dL (Hodges-Lehmann, 95% CI 2.9-5.0; LMM p < 0.001). Total exposure was 112 patient-months; EAIR for any-grade treatment-emergent adverse events was 8.0 per 100 patient-months. No ≥Grade 2 neurotoxicity or thrombosis occurred. In TDT patients with predefined luspatercept failure, adding low- to moderate-dose thalidomide was associated with improvements in hemoglobin levels and reductions in transfusion burden with favorable tolerability. These findings warrant prospective validation of this structured rescue approach.
2026-06-27 | Dapagliflozin in Patients with homozygous β-Thalassemia and Albuminuria.
Introduction Patients with homozygous β-thalassemia show continuously improved survival, which has contributed to the development of kidney complications, predominantly expressed as increased albuminuria. In particular, patients with transfusion-dependent thalassemia (TDT), frequently develop chronic kidney complications related to chronic anemia, iron overload, and exposure to iron chelation therapy. Although sodium-glucose co-transporter 2 inhibitors (SGLT-2is) have demonstrated renoprotective effects in patients with chronic kidney disease (CKD) from other causes, their efficacy in patients with homozygous β-thalassemia and established CKD remains unknown. Methods In this prospective, open-label study we investigated the impact of dapagliflozin (10 mg/day), in patients with homozygous β-thalassemia and an albumin to creatinine ratio (ACR)>30 mg/g. Study end-points included the effect on ACR and kidney function at 6 months after treatment initiation. Furthermore, we examined the effect on systolic (SBP) and diastolic blood pressure (DBP), and on urine monocyte chemoattractant protein-1 (MCP-1) and matrix metalloproteinase-9 (MMP-9) levels. Results Twelve patients with ACR>30 mg/g received dapagliflozin and 18 patients with normal ACR were followed up for 6 months. Twenty three healthy adult individuals age- and sex-matched to the β-thalassemia group were used as normal controls. Patients with ACR>30 mg/g showed a significant reduction of ACR and SBP at 6 months (p=0.034, p=0.025 respectively) while kidney function remained stable. Patients with homozygous β-thalassemia showed increased baseline urine MCP-1 levels, while MMP-9 showed no differences versus normal controls. Those, who received dapagliflozin exhibited a significant decrease in urine MCP-1 (p=0.022) while MMP-9 remained stable. There were no significant adverse events. Conclusion Dapagliflozin at a standard dose of 10 mg daily is safe and effectively reduces albuminuria and urinary MCP-1 in patients with homozygous β-thalassemia and established CKD, suggesting potential kidney anti-inflammatory effects. Further studies with larger cohorts and longer follow-up are needed to determine its impact on CKD progression and long-term outcomes.
gene therapies
2026-08-12 | 2026 Update on Clinical Trials in β-Thalassemia.
The therapeutic landscape of β-thalassemia has evolved rapidly over the past decade, shifting from a historical reliance on transfusion support and iron chelation toward disease-modifying and potentially curative therapies. This review summarizes the clinical development of novel treatments for both non-transfusion-dependent and transfusion-dependent β-thalassemia, including approved therapies, agents in active development, and programs that have been discontinued. Disease-modifying strategies have focused on improving ineffective erythropoiesis, correcting iron dysregulation, and restoring red blood cell metabolism. Luspatercept and mitapivat have demonstrated clinically meaningful improvements in hemoglobin levels and reduction of transfusion burden and are now approved in multiple jurisdictions. Additional pyruvate kinase activators, such as etavopivat, are undergoing clinical evaluation. Curative approaches have advanced substantially through gene addition, gene editing, and base editing technologies. Approved therapies, including betibeglogene autotemcel and exagamglogene autotemcel, have achieved high rates of durable transfusion independence, while emerging platforms aim to further improve efficacy, safety, and accessibility. At the same time, several promising approaches targeting fetal hemoglobin induction, iron metabolism, and ineffective erythropoiesis have failed to demonstrate sufficient clinical benefit despite preclinical proof of concept, highlighting the complexity of therapeutic development in β-thalassemia. Future priorities include refining patient selection, generating real-world and comparative effectiveness data, developing clinically meaningful response criteria, expanding pediatric access, and addressing the substantial cost and accessibility challenges associated with novel therapies.
2026-07-28 | Public knowledge, attitudes, and ethical views on CRISPR-Cas9 gene editing for genetic diseases in Taif, Saudi Arabia.
Public support for gene editing, particularly for therapeutic purposes, remains strong. Recently, the Ministry of Health in Saudi Arabia approved CRISPR-Cas9 for treating Sickle Cell Disease and beta thalassemia. This study aims to assess the Taif population's opinion on gene editing and their knowledge of genetic modification. In this cross-sectional study, a questionnaire was distributed online from March 2, 2024, to June 15, 2024, to 747 residents of Taif City aged 18 and older. Among the respondents, 14.7% reported that they or their family members suffer from a hereditary disease, and 65.7% either work or study in the healthcare field or have a family member involved in healthcare. Additionally, 50.7% had previously heard of genetic modification. Marital status, number of children, and education level did not significantly influence opinions on genetic editing, whereas affiliation with the healthcare field was significantly associated with greater acceptance (p = 0.023), while a family history of hereditary disease showed a trend toward significance (p = 0.055). Public opinion strongly supports using genetic editing to treat life-threatening diseases in adults and embryos (63.2% and 73.6%, respectively). However, opinions are more divided on non-disease traits. Many respondents expressed interest in enhancing intelligence (73.8%) and strength (75.8%), as well as altering height (67.8%) and hair color (60.7%). While support was strong for therapeutic use, opinions were divided on enhancement, reflecting ethical tension despite high interest in modifying non-disease traits. Notably, 50.7% believed that using genetic editing for non-medical purposes crosses ethical boundaries and exceeds nature's limits. Awareness of gene-editing techniques was not significantly associated with acceptance (p = 0.108). In conclusion, public acceptance of gene editing in Taif is high, particularly among healthcare-affiliated individuals. Increasing public awareness remains essential to bridge ethical concerns and support informed engagement.
2026-07-23 | Base editing for precision therapeutics.
Base editing (BE), the precise installation of single-nucleotide changes in DNA or RNA without inducing double-strand breaks, holds substantial therapeutic promise for correcting single-nucleotide variants, which constitute more than half of the known pathogenic genetic variants. Recent advances have improved base editor specificity, efficiency, and delivery, enabling clinically oriented procedures. Clinically, BE has shown early success or strong translational promise in sickle cell disease, β-thalassemia, leukemia (via CAR T and epitope engineering), hypercholesterolemia (PCSK9 and ANGPTL3), alpha-1-antitrypsin deficiency, and glycogen storage disease type Ia. Key remaining challenges include bystander editing within the activity window, residual off-target DNA and RNA editing, delivery constraints (payload size, tissue targeting, and redosing limits), immunogenicity, and the need for durable long-term safety evidence across relevant cell types and disease contexts. Continued technological refinements, careful preclinical validation, and rigorous clinical assessment will be essential to fully realize BE's transformative potential in precision medicine.
2026-07-17 | Update of the decision-making algorithm on selecting transfusion-dependent β-thalassemic patients for gene therapy approaches: joint consensus report on behalf of EHA-specialized working group and EBMT hemoglobinopathies working party.
β-thalassemia is a globally distributed hereditary red blood cell disorder. Up to now, clinical management of transfusion-dependent β-thalassemia (TDT) patients is still based on chronic transfusion combined with iron chelation therapy. Allogeneic hematopoietic cell transplantation potentially provides a cure, but few patients have an HLA-identical sibling, and optimal results are reported in patients ≤ 14 years. The European Hematology Association (EHA), through the EHA Scientific Working Group on Red Cells/Iron and the European Bone Marrow Transplantation (EBMT) group, has updated a 2021 EHA decision-making algorithm on evidence and expert consensus with the aim of identifying which patients with TDT could benefit from gene therapy (GT). Indeed, it is important to establish the patient setting for whom it is a priority, particularly in the early phase of real-world use outside experimental trials. Moreover, actual price, limited availability, and resource disposal constitute a further indication of a rational and progressive approach to this innovative treatment. In this expert consensus document, different clinical scenarios have been considered and analyzed for the possible impact on treatment outcome. This expert opinion provides dynamic, updatable, priority-based guidance for physicians taking care of TDT patients.
2026-06-21 | Genetic Mutations and Clinical Severity in Hemoglobin E/Beta-Thalassemia Patients in Bangladesh
Background and objective The phenotypically diverse presentation of hemoglobin (Hb) E/β-thalassemia is often attributed to coinheritance of β-globin (HBB) gene mutations. This study aimed to describe the genetic mutations and clinical severity of HbE/β-thalassemia patients from low-resource settings. Methods A total of 32 HbE/β-thalassemia patients were included in this cross-sectional study. Cases were confirmed by capillary Hb electrophoresis or high-performance liquid chromatography and were further analyzed alongside clinical information and ancestral data. The data collection period spanned from May 2019 to July 2020. Gene sequencing was performed using the Sanger sequencing method for mutational analysis, and Mahidol scoring was applied to assess clinical severity. Results The median age of the patients was 20 years (interquartile range (IQR): 17-22.5). Phenotypically, mild, moderate, and severe disease were observed in 12 (37.5%), 14 (43.8%), and six (18.8%) patients, respectively. Overall, 13 heterozygous mutations were identified in the HBB gene. Among these, IVS-1-5 (G>C) was the most common mutation (n = 17, 53.1%), and codon 30 (G>C) (n = 4, 12.5%) was the second most common mutation. The IVS-1-5 (G>C) mutation was significantly more frequent among patients with severe disease (p<0.001). Conclusions This study is one of the few to characterize clinical severity and genetic mutations in HbE/β-thalassemia patients in Bangladesh. The information on clinical severity patterns could be useful for determining service priorities and ensuring the proper allocation of limited resources.
proteins
2026-08-11 | A review on the role of Hepicidin hormone in beta thalassemia major disease
Thalassemia is a haemoglobin disorder that is inherited. One or more globin chains of haemoglobin tetramers are produced less frequently or not at all, which causes uncontrollably high RBC destruction and severe anemia. An imbalance in globin chain synthesis causes damage to red blood cells in thalassemia. Hepcidin is severely reduced in thalassemia, and any increase in hepcidin function benefits erythropoiesis and iron metabolism. Clinical trials have been conducted on synthetic hepcidin and hepcidin mimetics. Nevertheless, their efficacy/safety profile has not been satisfactory. When taking hepcidin directly as a medication, it appears to be challenging to prevent iron over-restricted erythropoiesis. Indirect methods are numerous and still evolving, each with pros and cons. Targeting erythroferrone, the primary inhibitor of hepcidin expression, is the best strategy because iron-loading anaemias significantly raise its plasma concentrations. The development of pharmacological agonists and antagonists as well as hepcidin diagnostics should enhance the management of iron diseases.
2026-08-10 | Precision Medicine in Transfusion-Dependent and Non-Transfusion-Dependent β-Thalassemia: Toward Personalized Diagnosis and Therapy.
β-thalassemia comprises a clinically heterogeneous group of disorders in which anemia severity, transfusion exposure, iron loading, and organ complications vary widely among individuals. This structured narrative review summarizes practical applications of precision medicine in transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT), with explicit attention to which strategies apply to each clinical category. Literature indexed in PubMed and Scopus from 2000 to 2025 was reviewed using terms related to thalassemia, precision medicine, magnetic resonance imaging (MRI), chelation tailoring, next-generation sequencing (NGS), fetal hemoglobin (HbF) modifiers, luspatercept, mitapivat, hepcidin, gene therapy, gene editing, and artificial intelligence (AI). Evidence was synthesized descriptively because interventions, outcomes, and populations were heterogeneous, and no pooled meta-analysis was performed. In TDT, precision care is centered on individualized transfusion planning, extended red-cell antigen matching, MRI-guided cardiac and hepatic iron monitoring, organ-directed chelation intensification, and selection of disease-modifying or curative approaches. In NTDT, precision care emphasizes accurate phenotype classification, MRI liver iron concentration, because serum ferritin may underestimate iron burden, selective chelation, surveillance for NTDT-specific complications, and individualized use of agents that improve anemia. Personalized chelation should include deferiprone, either alone or in combination, when cardiac iron is increased. Comprehensive molecular diagnosis should include HBB together with HBA1 and HBA2 assessment, while secondary and tertiary modifiers help explain phenotypic variability and complication risk. Hepcidin and growth differentiation factor 15 (GDF-15) are discussed as investigational biomarkers; transferrin saturation is not recommended for routine iron-overload assessment in thalassemia. AI currently has its strongest role in screening and diagnosis, whereas risk-stratification models remain exploratory. Equitable implementation requires standardized TDT/NTDT pathways, regional MRI and genomics access, longitudinal registries, and multidisciplinary interpretation.
2026-06-26 | Outcomes with luspatercept in patients with β-thalassemia: a systematic review and meta-analysis.
β-thalassaemia is a genetic blood disorder characterized by ineffective erythropoiesis and chronic anaemia, often requiring lifelong red blood cell (RBC) transfusions. Luspatercept, an erythroid maturation agent, has emerged as a potential therapy to reduce transfusion burden in affected adults. To assess the clinical efficacy and safety of luspatercept in managing adult patients with β-thalassemia. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating luspatercept in adult patients with β-thalassemia. A comprehensive search of PubMed, Scopus, Embase, Cochrane Library, and ClinicalTrials.gov was performed for studies published up to May 2025. Only English-language RCTs were included. Data were extracted on transfusion burden, hemoglobin response, and adverse events. Risk of bias was assessed using the Cochrane ROB 2 tool. Pooled estimates were calculated using a random-effects model with the Freeman-Tukey double arcsine transformation. Heterogeneity was assessed using the I² statistic. Out of 587 identified records, three RCTs and one single-arm trial (n = 608 patients) met the inclusion criteria. Of these, 447 patients received luspatercept and 161 received placebo. Luspatercept was associated with a ≥ 33% reduction in RBC transfusion burden in 58% (95% CI: 0.33-0.79) and a ≥ 50% reduction in 40% (95% CI: 0.25-0.58) of patients. Transfusion independence was achieved in 36% (95% CI: 0.13-0.69). Common adverse events included headache (32%), bone pain (33%), arthralgia (22%), and back pain (20%). Grade ≥ 3 adverse events occurred in 21% (95% CI: 0.09-0.41). Overall, luspatercept effectively reduced transfusion needs with an acceptable safety profile. Luspatercept significantly reduces transfusion burden in patients with β-thalassemia and demonstrates a manageable safety profile. These findings support luspatercept as an effective and well-tolerated therapeutic option that meaningfully reduces transfusion burden, potentially decreasing iron overload and improving quality of life for patients with β-thalassemia.
2026-04-27 | Dissecting polycomb complexes for enhanced fetal hemoglobin production.
Polycomb repressive complexes PRC1 and PRC2 regulate diverse developmental processes, including the fetal-to-adult switch in hemoglobin production, a process whose reversal is a goal for the treatment of sickle cell disease and β-thalassemia. PRC inhibitors show promise for various disorders, but use is limited because of pleiotropic PRC activities. We explored whether fetal hemoglobin (HbF) can be reactivated in adult erythroid cells by selective perturbations of PRC1 or PRC2 components without complete loss of PRC function. A high-density CRISPR-Cas9 mutagenesis screen identified a region in the EZH2 subunit where Cas9 induced exon 14 skipping (EZH2Δ14). EZH2Δ14, which lacks a portion of the CXC domain, relieves HbF repression while largely maintaining cellular fitness. EZH2Δ14 retains H3K27 methylation and repression of a PRC target gene subset. Experiments in cells derived from mice bearing human β-globin genes confirm that pathways mediating EZH2 control of HbF expression can function in a mouse model of HBG switching. These findings demonstrate that partial disruption of PRC can yield selective phenotypes, highlighting the therapeutic potential of targeting non-enzymatic domains within chromatin-modifying complexes.
2026-03-20 | Patient-Reported Outcomes With Luspatercept Through 5 Years of Treatment in Patients With Non-Transfusion-Dependent β-Thalassemia Treated in the BEYOND Trial.
In the phase 2, double-blind, randomized controlled BEYOND trial (NCT03342404), luspatercept increased hemoglobin levels in patients with non-transfusion-dependent β-thalassemia (NTDT). This study assessed long-term effects of luspatercept on patient-reported outcomes (PROs), using data from BEYOND and patients who continued luspatercept treatment in the phase 3b long-term follow-up (LTFU) study (NCT04064060). In BEYOND, patients received luspatercept or placebo Q3W for ≥ 48 weeks. PRO instruments included NTDT-PRO (BEYOND only), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), and 36-Item Short Form Survey (SF-36). Mixed-effects models with repeated measures estimated least squares mean changes from baseline in PROs. PROs were evaluable in 144 patients (luspatercept 95, placebo 49) from BEYOND and 58 (luspatercept) from LTFU. Luspatercept improved NTDT-PRO tiredness/weakness and shortness of breath domain, FACIT-F fatigue subscale, and SF-36 vitality scores versus placebo through double-blind treatment (generally maintained through week 96). In LTFU patients, significant, meaningful improvements from baseline in FACIT-F fatigue subscale and SF-36 vitality scores were observed within 12 weeks of treatment initiation and maintained for up to 5 years. Other FACIT-F and SF-36 domains improved or were maintained throughout LTFU. Luspatercept offers rapid and durable benefits by improving anemia-related symptoms and quality of life in patients with NTDT. Trial Registration: ClinicalTrials.gov Identifier: NCT03342404; NCT04064060.
cell therapies
2026-06-10 | CRISPR application in hematological disorders: from bench to bedside.
Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas genome editing has advanced from an experimental tool to a clinically validated therapeutic platform in hematology. Landmark successes in inherited blood diseases including sickle cell disease, β-thalassemia, and severe combined immunodeficiency, have demonstrated that precise and durable genetic modifications can be safely and effectively implemented in human hematopoietic cells, positioning hematology at the forefront of translational genome editing. Beyond monogenic disease, CRISPR-based approaches are transforming both the biological understanding and treatment of hematologic malignancies by enabling systematic interrogation of cancer dependencies, functional mapping of genetic vulnerabilities, and mechanism-driven target validation, including in vivo and immune-relevant contexts. In parallel, therapeutic applications are emerging through the development of engineered cellular therapies, including edited autologous and allogeneic immune effector cells designed to enhance antitumor efficacy, persistence, and immune evasion. This review synthesizes recent CRISPR-based advances across benign and malignant hematologic diseases. We compare major editing modalities, including nuclease-mediated disruption, base editing, prime editing, and CRISPR-based transcriptional modulation, and highlight key preclinical studies alongside emerging clinical trial data. We also discuss translational challenges that currently limit broader clinical adoption, including delivery and manufacturing scalability, off-target and genotoxicity risks, tumor and immune heterogeneity, and the long-term durability and fitness of edited cell populations. Finally, we outline priorities for the next phase of the field, emphasizing how continued innovation in CRISPR technologies may enable increasingly precise, durable, and mechanism-informed therapeutic strategies in hematology.
2026-06-08 | Correction of Ineffective Erythropoiesis and Normalization of Iron Homeostasis After Exagamglogene Autotemcel in Transfusion-Dependent β-Thalassemia.
Exagamglogene autotemcel (exa-cel) is a one-time, ex vivo, CRISPR-Cas9 gene edited cell therapy approved for patients with transfusion dependent β-thalassemia (TDT) aged 12-35 years. In a Phase 3 study (CLIMB THAL-111), exa-cel treatment resulted in reactivation of fetal hemoglobin and increases in total hemoglobin, leading to transfusion independence in 91% of participants. Here, we report on the impact of exa-cel treatment on measures of ineffective erythropoiesis and iron homeostasis, which were secondary and exploratory endpoints in CLIMB THAL-111 and the CLIMB-131 long-term follow-up study. Prior to exa-cel infusion, all participants were receiving regular red blood cell transfusions and iron chelation therapy. At time of data cut (April 2025), 98% of participants (55 of 56) had been transfusion independent for ≥ 12 months and 38 (68%) had discontinued iron removal therapy (mean duration off iron removal therapy 19.4 months). Following transfusion independence and cessation of iron removal therapy, erythroferrone concentrations decreased and hepcidin levels normalized in all participants, indicating correction of ineffective erythropoiesis and restoration of iron homeostasis. Further supporting this finding, improvements and trends toward normalization were seen in key erythropoiesis biomarkers, including erythropoietin levels, reticulocyte counts, and soluble transferrin receptor concentrations. Iron overload biomarkers, including ferritin, liver iron concentration, and cardiac T2*, decreased and then remained stable throughout follow-up, even after cessation of iron removal therapy. These results demonstrate restoration of effective erythropoiesis and iron homeostasis after exa-cel infusion in the setting of transfusion independence following reactivation of fetal hemoglobin. (CLIMB THAL-111 and CLIMB-131; Clinical Trials.gov numbers NCT03655678 and NCT04208529).
2026-06-05 | Comparative study of hemoglobin changes following transfusion of fresh and old blood in patients with thalassemia referred to Bahrami Hospital.
Thalassemia major is a severe hemoglobinopathy that requires blood transfusion; however, long term blood transfusion might increase morbidity and mortality. Hemoglobin (Hb) after transfusion determines the need for next transfusion. There is controversy regarding the effect of fresh packed RBC compared to old packed RBC transfusion on Hb. This study compared hemoglobin changes following transfusion between fresh and old packed RBC in transfusion-related thalassemia (TRT) patients. In this cohort study, 140 TRT patients (age > 5years) referred to Bahrami Children's Hospital in mid-2013 were included. Equal number (n = 70) of age and gender matched TRT patients with exposure to fresh (stored for less than 7 days) and old (stored for more than 7 days) packed RBC transfusion were followed for 14 days. In both groups, demographic information (age, sex) were recorded at enrolment. Physical examination data and blood parameters, including red blood cells (RBC), white blood cells (WBC), platelets (PLT), Hb, ferritin, transferrin, total iron binding capacity and bilirubin at baseline and follow up. Time-group interaction was significant only for WBC (p < 0.001) and Hb (p = 0.029) indicating that fresh packed RBC transfusion resulted in higher Hb and lower WBC at follow up compared to baseline levels. Among the baseline variables only fresh packed RBC transfusion was found to increase the odds of having Hb of at least 1 mg/dL higher than baseline (OR = 15.465, p < 0.001). Fresh packed RBC transfusion might increase the interval between transfusions due to more Hb elevation rate after transfusion in thalassemia major.
2026-06-02 | [Research Progress on the Bone Marrow Microenvironment in Beta-Thalassemia --Review].
Thalassemia is one of the most common and harmful single-gene recessive disorders in the clinic. It is characterized by impaired or absent production of one globin chain of hemoglobin in adults. The most common form is beta-thalassemia, which is associated with defects in the production of beta-globin chain, resulting in an imbalance in the ratio of alpha-globin to beta-globin. As a result, unbound free alpha-globin chains precipitated in red blood cell precursors, resulting in iron overload, ineffective red blood cell production, and changes in mesenchymal stem cells, osteoblasts, osteoclasts, and other associated cells. Among them, iron overload and ineffective red blood cell production will destroy the bone marrow microenvironment, which will cause further damage to the hematopoietic system. Therefore, the correction of the bone marrow microenvironment plays an important role in the treatment of thalassemia. This review summarizes studies on the destruction of the bone marrow microenvironment in beta-thalassemia, treatment options for improving the microenvironment and stem cell transplantation.
2026-05-05 | Genetic Engineering in Hematopoietic Stem Cells for β-Hemoglobinopathies Treatment: Advances, Challenges, and Clinical Translation.
β-hemoglobinopathies rank among the most prevalent inherited blood disorders globally. Traditional management strategies are primarily palliative and often associated with significant challenges, including iron overload and limited long-term efficacy. Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative option for transfusion-dependent patients, but its broader applicability is constrained by factors that limit its use. Utilizing viral vectors and gene-editing tools, particularly CRISPR-Cas9 technology, researchers have developed therapies that target the root causes of these disorders. These innovative approaches have demonstrated substantial therapeutic potential, accompanied by favorable safety profiles, in clinical settings. Since the initial investigations, the genome editing tool has rapidly advanced for genetic abnormalities, particularly monogenic blood diseases, including β-hemoglobinopathies. This method suggests an approach with lower concerns in viral gene integration and insertional mutagenesis issues. This review comprehensively surveys the therapeutic strategies for β-thalassemia and sickle cell disease (SCD) currently in preclinical and clinical development, with a focus on the evolving treatment paradigm. Looking forward, critical research priorities include optimizing the efficiency and specificity of gene-editing platforms and pioneering novel delivery systems to guarantee both therapeutic efficacy and clinical safety.
other
2026-06-12 | Cyclic Fevers in Pregnancy: A Case of Parvovirus-Related Hemophagocytic Lymphohistiocytosis.
Parvovirus B19 typically causes mild symptoms in healthy adults, including fever, rash, and arthralgias. Certain immunocompromised adult populations, including those with immunodeficiencies or hematologic disease, are at risk of clinically significant complications, including transient aplastic crisis. Further, in pregnant patients, there is a risk of transplacental viral transmission, which may lead to severe fetal anemia, nonimmune hydrops fetalis, and intrauterine fetal demise. The clinical course of parvovirus B19 in pregnant patients with underlying hematologic disease has not been well reported. In this case report, we present a 27-year-old pregnant patient with sickle cell beta thalassemia who was infected with parvovirus B19 at 20 weeks of gestation. She experienced a prolonged hospitalization characterized by persistent maternal vaso-occlusive crisis with concomitant transient aplastic crisis. There was suspected vertical transmission of the virus, leading to concern for severe fetal anemia and termination of the pregnancy. The patient continued to have cyclic fevers, bicytopenia, and a constellation of laboratory findings leading to a diagnosis of postviral hemophagocytic lymphohistiocytosis (HLH). She was successfully treated with pulse dose corticosteroids and an Interleukin-1 receptor antagonist with subsequent improvement of her symptoms and laboratory markers. This report highlights the distinct diagnostic and management challenges of parvovirus B19 in pregnant patients with comorbid hematologic disease, including a rare but serious sequela of the infection, and the risk for severe maternal and fetal complications.
2026-06-05 | Use of romosozumab for osteoporosis in β-thalassemia major.
Thalassemia bone disease is a common and severe complication of β-thalassemia major (TM), resulting from marrow expansion, hormonal deficiencies, including hypogonadism, iron toxicity, and increased bone turnover. These factors contribute to reduced BMD and increased susceptibility to minimal trauma fracture (MTF). Optimizing transfusions and iron chelation therapy, management of hormonal deficiencies, and antiresorptive therapies are the cornerstone of management. We report the use of romosozumab in 2 patients with TM and severe osteoporosis. This is the first case series describing the efficacy of romosozumab in the treatment of osteoporosis in patients with TM. After completion of 12 mo of monthly romosozumab, DXA scan demonstrated significant improvements in BMD despite previous prolonged exposure to antiresorptive therapy in both subjects. This represents a promising treatment option in patients with TM and osteoporosis.
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.
2026-04-09 | Mechanisms of resistance to Tmprss6 antisense oligonucleotides in a mouse model of β-thalassemia.
Non-transfusion dependent β-thalassemia (NTDT) is characterized by ineffective erythropoiesis, suppression of hepcidin, and iron overload, which is a major cause of morbidity and mortality. Hepatic protease Tmprss6 regulates hepcidin by modulating BMP/Smad signaling. Suppression of Tmprss6 in the mouse model of NTDT (Th3 mice), increased hepcidin and improved disease outcomes, but similar benefits have not been reported in human trials. We hypothesized that the resistance to the effects of anti-TMPRSS6 treatment in patients with NTDT may be caused by high erythroferrone (ERFE) concentrations and more severe iron overload, both known to modulate BMP/Smad signaling in hepatocytes. We therefore examined how ERFE and iron overload modulate the effects of Tmprss6 antisense oligonucleotides (ASO) in mouse models.We treated ERFE-overexpressing Th3 mice (T-E(M)) and their littermates (wild-type, Th3, and Erfe-overexpressing E(M) mice) with Tmprss6 ASO or non-targeting ASO for 4 weeks. Tmprss6 ASO increased phospho-Smad1/5/8 and hepcidin levels, decreased splenomegaly, reduced extramedullary erythropoiesis and improved iron parameters in Th3 mice but not in T-E(M) mice, despite similar Tmprss6 decrease. To determine whether iron overload alone blunted the effects of Tmprss6 ASO, we assessed the responses of C57BL/6 mice after 10 mg of iron dextran or 5000 ppm high iron diet. Unlike iron-adequate mice, iron-overloaded mice already had high phospho-Smad and hepcidin, with no further increase after Tmprss6 ASO treatment, and no effect on erythroid or iron parameters.Higher ERFE concentrations and more severe iron overload may be responsible for diminished benefits of Tmprss6 ASO in human NTDT.
2026-02-13 | miRNA-Mediated Regulation of γ-Globin to β-Globin Switching: Therapeutic Potential in β-Hemoglobinopathies.
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.
small molecules
2026-08-01 | Structure-guided targeting of the GATAD2A-CHD4 interaction within the MBD2-NuRD complex results in high levels of HbF in adult erythroid cells.
Fetal hemoglobin (HbF) expression is silenced postnatally in adult erythroid cells. Sufficiently increased expression of HbF has been shown to overcome the pathophysiologic sequelae of both sickle cell disease and beta-thalassemia. As the MBD2a-NuRD chromatin remodeling complex is required for silencing of HbF, the present studies were aimed at exploring a potential therapeutic approach for disrupting this complex. AlphaFold 3 and a recent crystal structure were employed to predict the critical interaction domains linking GATAD2A in the histone deacetylase core subcomplex (HDCC) of NuRD and the CHD4 ATPase which has been shown to be required for silencing of the fetal gamma-globin ( HBG ) genes. The two predicted critical domains, the CR2 helical domain of GATAD2A and the C-terminal domains 1 and 2 (C1b and C2ab) of CHD4, were validated by in vitro biophysical studies. Mutation of two amino acids in the CR2 helical domain of the endogenous GATAD2A gene in HUDEP-2 cells resulted in dissociation of CHD4, loss of repressive chromatin over the HBG promoter and ~40% HbF levels compared to < 1% in control cells. Strikingly, enforced expression of a peptide containing the helical portion of the CR2 domain of GATAD2A in both HUDEP-2 cells and primary adult erythroid cells resulted in high levels of HbF, with up to ~75% HbF compared to mutant peptide control level of ~9% in the latter without perturbing erythroid differentiation. These results suggest that targeting the critical interaction domains of GATAD2A and CHD4 with a macrocyclic peptide or small molecule may lead to much needed small molecule therapeutics for sickle cell disease. Association of CHD4 with the HDCC core of the MBD2-NuRD chromatin remodeling complex is required for silencing of HbF expression in adult human erythroid cellsGenetic alteration or enforced peptide expression of a critical helical domain of GATAD2A results in dissociation of CHD4 from the MBD2-NuRD complex and high-level expression of HbF.
2026-07-23 | Fludarabine, Busulfan, Thiotepa, and Melphalan: A Novel Low-Toxicity Myeloablative Conditioning Regimen for Haploidentical HSCT in Children and Adolescents Aged ≥7 Years With Transfusion-Dependent β-Thalassemia.
Graft failure and transplant-related mortality remain major barriers to haploidentical donor hematopoietic stem cell transplantation (HID-HSCT) in children and adolescents aged ≥7 years with transfusion-dependent thalassemia (TDT). Thus, a novel low-toxicity myeloablative conditioning regimen was developed to improve transplantation outcomes. In this prospective, single-center study (clinical trial registration ChiCTR2300071890), TDT patients aged ≥7 years were enrolled to evaluate the safety and efficacy of a conditioning regimen comprising fludarabine, busulfan, thiotepa, and melphalan (F-BMT). For HID recipients, graft-versus-host disease (GVHD) prophylaxis included half-dose PTCY combined with the in vivo T-cell depletion (porcine anti-human lymphocyte immunoglobulin or rabbit anti-human thymocyte globulin), along with other immunosuppressive agents. The primary endpoint was the 2-year thalassemia-free survival (TFS) rate. From June 2023 to August 2024, 29 TDT patients aged ≥7 years undergoing HID-HSCT were enrolled (14 males, 15 females). The 2-year TFS and overall survival rates were both 93.1%. Neutrophil and platelet engraftment were achieved in all patients, with no reported graft failure. The observed incidence of Grade II-IV acute GVHD was 17.2%. Chronic GVHD occurred in 6.9% of the patients. Regimen-related toxicities were manageable, with only one case of sinusoidal obstruction syndrome and three cases of hemorrhagic cystitis, all of which resolved with supportive treatment. No mixed chimerism was observed. The F-BMT regimen provides effective myeloablation with reduced toxicity, supporting its feasibility for HID-HSCT in TDT patients aged ≥7 years.
2026-07-08 | Unlocking thalidomide response as a hemoglobin F augmentation agent in transfusion-dependent β-thalassemia: the genetic impact of BCL11A, HBS1L-MYB, and XmnI polymorphism.
Thalidomide has been found to augment fetal hemoglobin (HbF) synthesis, thereby decreasing transfusion requirements in patients with β-thalassemia. Elevated fetal hemoglobin, influenced by genetic polymorphisms, can significantly modify the clinical severity of β-thalassemia. The study aimed to determine the frequency of the XmnI (rs7482144), BCL11A (rs766432), and HBS1L-MYB (rs9399137) polymorphisms in patients with β-thalassemia and to evaluate their association with the response to thalidomide therapy. This prospective observational study was conducted at Baqai Medical university. One hundred transfusion-dependent β-thalassemia patients on low-dose thalidomide (2 mg/kg/day) were enrolled from Muhammadi blood bank and diagnostics center, Karachi. The outcome measures of response were defined as an increase in hemoglobin (Hb) levels and reduction in blood transfusion frequency following three months of thalidomide treatment, based on which participants were classified as excellent responders, good responders, or non-responders. The Xmn1 (rs7482144), BCL11A (rs766432) and HBS1L-MYB (rs9399137) single nucleotide polymorphisms (SNPs) were detected using the Amplification Refractory Mutation System Polymerase chain reaction (ARMS-PCR). Among the 100 patients, the rs7482144 was present in 68% of cases, rs766432 in 47%, and rs9399137 in 20%. Following three months of thalidomide treatment, Hb levels (9.3 ± 1.5 g/dl) increased significantly compared to baseline levels (5.4 ± 1.6 g/dl) (p<.001). An overall response rate of 87% was recorded. Results showed that minor allele-containing genotypes of three SNPs were significantly associated with an increased likelihood of excellent response [rs7482144: p=.001, RR:1.733; rs766432: p<.001, RR:3.070; rs9399137: p=.023, RR:4.043]. Post-treatment HbF increment was correlated with the cumulative number of minor alleles across the three significant SNPs among excellent responders, with HbF being lower in individuals having ≤ 1 polymorphism (74.0%±19.2%) compared with those carrying 2 (83.0%±8.6%; p=.033) or 3 polymorphisms (97.3%±0.5%; p=.01). Our study indicates that SNPs within HBG2(rs7482144), BCL11A(rs766432), and HBS1L-MYB (rs9399137) region are strongly associated with thalidomide responsiveness in β-thalassemia patients, with the overall number of minor alleles serving as a potential marker for therapeutic response.
2026-07-04 | Low- to moderate-dose thalidomide combination rescue after luspatercept failure in transfusion-dependent β-thalassemia: a real-world cohort study.
A proportion of transfusion-dependent β-thalassemia (TDT) patients show suboptimal or heterogeneous response to luspatercept. We explored a structured rescue approach by adding low- to moderate-dose thalidomide after predefined luspatercept failure in real-world practice. This study was a single-center retrospective cohort study. Adults with TDT on luspatercept who met predefined criteria for suboptimal response (failure to achieve ≥ 33% reduction in RBC units over a 12-week window versus each patient's baseline 12-week window, or failure to increase Hb by ≥ 1.0 g/dL under an unchanged transfusion trigger) received thalidomide 25-50 mg once daily while continuing luspatercept. Primary endpoint was 12-week transfusion independence (TI), defined as no transfusion for 12 consecutive weeks and Hb ≥ 9.0 g/dL. Secondary endpoints included ≥ 33%/≥50% reductions in RBC units over matched 12-week windows, longitudinal Hb change, and safety graded by CTCAE v5.0 and reported as exposure-adjusted incidence rates. Eleven patients were included (median age 23 years; female 45.5%; β⁰/β⁰ 18.2%; prior splenectomy 63.6%). Twelve-week transfusion independence (TI) was achieved in 4/11 patients (36.4%; 95% CI 15.2-64.6). Proportions with ≥ 33% and ≥ 50% reductions in RBC units over matched 12-week windows were 45.5% (95% CI 21.3-72.0) and 45.5% (95% CI 21.3-72.0), respectively. Hemoglobin increased by 4.0 g/dL (Hodges-Lehmann, 95% CI 2.9-5.0; LMM p < 0.001). Total exposure was 112 patient-months; EAIR for any-grade treatment-emergent adverse events was 8.0 per 100 patient-months. No ≥Grade 2 neurotoxicity or thrombosis occurred. In TDT patients with predefined luspatercept failure, adding low- to moderate-dose thalidomide was associated with improvements in hemoglobin levels and reductions in transfusion burden with favorable tolerability. These findings warrant prospective validation of this structured rescue approach.
2026-06-27 | Dapagliflozin in Patients with homozygous β-Thalassemia and Albuminuria.
Introduction Patients with homozygous β-thalassemia show continuously improved survival, which has contributed to the development of kidney complications, predominantly expressed as increased albuminuria. In particular, patients with transfusion-dependent thalassemia (TDT), frequently develop chronic kidney complications related to chronic anemia, iron overload, and exposure to iron chelation therapy. Although sodium-glucose co-transporter 2 inhibitors (SGLT-2is) have demonstrated renoprotective effects in patients with chronic kidney disease (CKD) from other causes, their efficacy in patients with homozygous β-thalassemia and established CKD remains unknown. Methods In this prospective, open-label study we investigated the impact of dapagliflozin (10 mg/day), in patients with homozygous β-thalassemia and an albumin to creatinine ratio (ACR)>30 mg/g. Study end-points included the effect on ACR and kidney function at 6 months after treatment initiation. Furthermore, we examined the effect on systolic (SBP) and diastolic blood pressure (DBP), and on urine monocyte chemoattractant protein-1 (MCP-1) and matrix metalloproteinase-9 (MMP-9) levels. Results Twelve patients with ACR>30 mg/g received dapagliflozin and 18 patients with normal ACR were followed up for 6 months. Twenty three healthy adult individuals age- and sex-matched to the β-thalassemia group were used as normal controls. Patients with ACR>30 mg/g showed a significant reduction of ACR and SBP at 6 months (p=0.034, p=0.025 respectively) while kidney function remained stable. Patients with homozygous β-thalassemia showed increased baseline urine MCP-1 levels, while MMP-9 showed no differences versus normal controls. Those, who received dapagliflozin exhibited a significant decrease in urine MCP-1 (p=0.022) while MMP-9 remained stable. There were no significant adverse events. Conclusion Dapagliflozin at a standard dose of 10 mg daily is safe and effectively reduces albuminuria and urinary MCP-1 in patients with homozygous β-thalassemia and established CKD, suggesting potential kidney anti-inflammatory effects. Further studies with larger cohorts and longer follow-up are needed to determine its impact on CKD progression and long-term outcomes.
gene therapies
2026-08-12 | 2026 Update on Clinical Trials in β-Thalassemia.
The therapeutic landscape of β-thalassemia has evolved rapidly over the past decade, shifting from a historical reliance on transfusion support and iron chelation toward disease-modifying and potentially curative therapies. This review summarizes the clinical development of novel treatments for both non-transfusion-dependent and transfusion-dependent β-thalassemia, including approved therapies, agents in active development, and programs that have been discontinued. Disease-modifying strategies have focused on improving ineffective erythropoiesis, correcting iron dysregulation, and restoring red blood cell metabolism. Luspatercept and mitapivat have demonstrated clinically meaningful improvements in hemoglobin levels and reduction of transfusion burden and are now approved in multiple jurisdictions. Additional pyruvate kinase activators, such as etavopivat, are undergoing clinical evaluation. Curative approaches have advanced substantially through gene addition, gene editing, and base editing technologies. Approved therapies, including betibeglogene autotemcel and exagamglogene autotemcel, have achieved high rates of durable transfusion independence, while emerging platforms aim to further improve efficacy, safety, and accessibility. At the same time, several promising approaches targeting fetal hemoglobin induction, iron metabolism, and ineffective erythropoiesis have failed to demonstrate sufficient clinical benefit despite preclinical proof of concept, highlighting the complexity of therapeutic development in β-thalassemia. Future priorities include refining patient selection, generating real-world and comparative effectiveness data, developing clinically meaningful response criteria, expanding pediatric access, and addressing the substantial cost and accessibility challenges associated with novel therapies.
2026-07-28 | Public knowledge, attitudes, and ethical views on CRISPR-Cas9 gene editing for genetic diseases in Taif, Saudi Arabia.
Public support for gene editing, particularly for therapeutic purposes, remains strong. Recently, the Ministry of Health in Saudi Arabia approved CRISPR-Cas9 for treating Sickle Cell Disease and beta thalassemia. This study aims to assess the Taif population's opinion on gene editing and their knowledge of genetic modification. In this cross-sectional study, a questionnaire was distributed online from March 2, 2024, to June 15, 2024, to 747 residents of Taif City aged 18 and older. Among the respondents, 14.7% reported that they or their family members suffer from a hereditary disease, and 65.7% either work or study in the healthcare field or have a family member involved in healthcare. Additionally, 50.7% had previously heard of genetic modification. Marital status, number of children, and education level did not significantly influence opinions on genetic editing, whereas affiliation with the healthcare field was significantly associated with greater acceptance (p = 0.023), while a family history of hereditary disease showed a trend toward significance (p = 0.055). Public opinion strongly supports using genetic editing to treat life-threatening diseases in adults and embryos (63.2% and 73.6%, respectively). However, opinions are more divided on non-disease traits. Many respondents expressed interest in enhancing intelligence (73.8%) and strength (75.8%), as well as altering height (67.8%) and hair color (60.7%). While support was strong for therapeutic use, opinions were divided on enhancement, reflecting ethical tension despite high interest in modifying non-disease traits. Notably, 50.7% believed that using genetic editing for non-medical purposes crosses ethical boundaries and exceeds nature's limits. Awareness of gene-editing techniques was not significantly associated with acceptance (p = 0.108). In conclusion, public acceptance of gene editing in Taif is high, particularly among healthcare-affiliated individuals. Increasing public awareness remains essential to bridge ethical concerns and support informed engagement.
2026-07-23 | Base editing for precision therapeutics.
Base editing (BE), the precise installation of single-nucleotide changes in DNA or RNA without inducing double-strand breaks, holds substantial therapeutic promise for correcting single-nucleotide variants, which constitute more than half of the known pathogenic genetic variants. Recent advances have improved base editor specificity, efficiency, and delivery, enabling clinically oriented procedures. Clinically, BE has shown early success or strong translational promise in sickle cell disease, β-thalassemia, leukemia (via CAR T and epitope engineering), hypercholesterolemia (PCSK9 and ANGPTL3), alpha-1-antitrypsin deficiency, and glycogen storage disease type Ia. Key remaining challenges include bystander editing within the activity window, residual off-target DNA and RNA editing, delivery constraints (payload size, tissue targeting, and redosing limits), immunogenicity, and the need for durable long-term safety evidence across relevant cell types and disease contexts. Continued technological refinements, careful preclinical validation, and rigorous clinical assessment will be essential to fully realize BE's transformative potential in precision medicine.
2026-07-17 | Update of the decision-making algorithm on selecting transfusion-dependent β-thalassemic patients for gene therapy approaches: joint consensus report on behalf of EHA-specialized working group and EBMT hemoglobinopathies working party.
β-thalassemia is a globally distributed hereditary red blood cell disorder. Up to now, clinical management of transfusion-dependent β-thalassemia (TDT) patients is still based on chronic transfusion combined with iron chelation therapy. Allogeneic hematopoietic cell transplantation potentially provides a cure, but few patients have an HLA-identical sibling, and optimal results are reported in patients ≤ 14 years. The European Hematology Association (EHA), through the EHA Scientific Working Group on Red Cells/Iron and the European Bone Marrow Transplantation (EBMT) group, has updated a 2021 EHA decision-making algorithm on evidence and expert consensus with the aim of identifying which patients with TDT could benefit from gene therapy (GT). Indeed, it is important to establish the patient setting for whom it is a priority, particularly in the early phase of real-world use outside experimental trials. Moreover, actual price, limited availability, and resource disposal constitute a further indication of a rational and progressive approach to this innovative treatment. In this expert consensus document, different clinical scenarios have been considered and analyzed for the possible impact on treatment outcome. This expert opinion provides dynamic, updatable, priority-based guidance for physicians taking care of TDT patients.
2026-06-21 | Genetic Mutations and Clinical Severity in Hemoglobin E/Beta-Thalassemia Patients in Bangladesh
Background and objective The phenotypically diverse presentation of hemoglobin (Hb) E/β-thalassemia is often attributed to coinheritance of β-globin (HBB) gene mutations. This study aimed to describe the genetic mutations and clinical severity of HbE/β-thalassemia patients from low-resource settings. Methods A total of 32 HbE/β-thalassemia patients were included in this cross-sectional study. Cases were confirmed by capillary Hb electrophoresis or high-performance liquid chromatography and were further analyzed alongside clinical information and ancestral data. The data collection period spanned from May 2019 to July 2020. Gene sequencing was performed using the Sanger sequencing method for mutational analysis, and Mahidol scoring was applied to assess clinical severity. Results The median age of the patients was 20 years (interquartile range (IQR): 17-22.5). Phenotypically, mild, moderate, and severe disease were observed in 12 (37.5%), 14 (43.8%), and six (18.8%) patients, respectively. Overall, 13 heterozygous mutations were identified in the HBB gene. Among these, IVS-1-5 (G>C) was the most common mutation (n = 17, 53.1%), and codon 30 (G>C) (n = 4, 12.5%) was the second most common mutation. The IVS-1-5 (G>C) mutation was significantly more frequent among patients with severe disease (p<0.001). Conclusions This study is one of the few to characterize clinical severity and genetic mutations in HbE/β-thalassemia patients in Bangladesh. The information on clinical severity patterns could be useful for determining service priorities and ensuring the proper allocation of limited resources.
proteins
2026-08-11 | A review on the role of Hepicidin hormone in beta thalassemia major disease
Thalassemia is a haemoglobin disorder that is inherited. One or more globin chains of haemoglobin tetramers are produced less frequently or not at all, which causes uncontrollably high RBC destruction and severe anemia. An imbalance in globin chain synthesis causes damage to red blood cells in thalassemia. Hepcidin is severely reduced in thalassemia, and any increase in hepcidin function benefits erythropoiesis and iron metabolism. Clinical trials have been conducted on synthetic hepcidin and hepcidin mimetics. Nevertheless, their efficacy/safety profile has not been satisfactory. When taking hepcidin directly as a medication, it appears to be challenging to prevent iron over-restricted erythropoiesis. Indirect methods are numerous and still evolving, each with pros and cons. Targeting erythroferrone, the primary inhibitor of hepcidin expression, is the best strategy because iron-loading anaemias significantly raise its plasma concentrations. The development of pharmacological agonists and antagonists as well as hepcidin diagnostics should enhance the management of iron diseases.
2026-08-10 | Precision Medicine in Transfusion-Dependent and Non-Transfusion-Dependent β-Thalassemia: Toward Personalized Diagnosis and Therapy.
β-thalassemia comprises a clinically heterogeneous group of disorders in which anemia severity, transfusion exposure, iron loading, and organ complications vary widely among individuals. This structured narrative review summarizes practical applications of precision medicine in transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT), with explicit attention to which strategies apply to each clinical category. Literature indexed in PubMed and Scopus from 2000 to 2025 was reviewed using terms related to thalassemia, precision medicine, magnetic resonance imaging (MRI), chelation tailoring, next-generation sequencing (NGS), fetal hemoglobin (HbF) modifiers, luspatercept, mitapivat, hepcidin, gene therapy, gene editing, and artificial intelligence (AI). Evidence was synthesized descriptively because interventions, outcomes, and populations were heterogeneous, and no pooled meta-analysis was performed. In TDT, precision care is centered on individualized transfusion planning, extended red-cell antigen matching, MRI-guided cardiac and hepatic iron monitoring, organ-directed chelation intensification, and selection of disease-modifying or curative approaches. In NTDT, precision care emphasizes accurate phenotype classification, MRI liver iron concentration, because serum ferritin may underestimate iron burden, selective chelation, surveillance for NTDT-specific complications, and individualized use of agents that improve anemia. Personalized chelation should include deferiprone, either alone or in combination, when cardiac iron is increased. Comprehensive molecular diagnosis should include HBB together with HBA1 and HBA2 assessment, while secondary and tertiary modifiers help explain phenotypic variability and complication risk. Hepcidin and growth differentiation factor 15 (GDF-15) are discussed as investigational biomarkers; transferrin saturation is not recommended for routine iron-overload assessment in thalassemia. AI currently has its strongest role in screening and diagnosis, whereas risk-stratification models remain exploratory. Equitable implementation requires standardized TDT/NTDT pathways, regional MRI and genomics access, longitudinal registries, and multidisciplinary interpretation.
2026-06-26 | Outcomes with luspatercept in patients with β-thalassemia: a systematic review and meta-analysis.
β-thalassaemia is a genetic blood disorder characterized by ineffective erythropoiesis and chronic anaemia, often requiring lifelong red blood cell (RBC) transfusions. Luspatercept, an erythroid maturation agent, has emerged as a potential therapy to reduce transfusion burden in affected adults. To assess the clinical efficacy and safety of luspatercept in managing adult patients with β-thalassemia. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating luspatercept in adult patients with β-thalassemia. A comprehensive search of PubMed, Scopus, Embase, Cochrane Library, and ClinicalTrials.gov was performed for studies published up to May 2025. Only English-language RCTs were included. Data were extracted on transfusion burden, hemoglobin response, and adverse events. Risk of bias was assessed using the Cochrane ROB 2 tool. Pooled estimates were calculated using a random-effects model with the Freeman-Tukey double arcsine transformation. Heterogeneity was assessed using the I² statistic. Out of 587 identified records, three RCTs and one single-arm trial (n = 608 patients) met the inclusion criteria. Of these, 447 patients received luspatercept and 161 received placebo. Luspatercept was associated with a ≥ 33% reduction in RBC transfusion burden in 58% (95% CI: 0.33-0.79) and a ≥ 50% reduction in 40% (95% CI: 0.25-0.58) of patients. Transfusion independence was achieved in 36% (95% CI: 0.13-0.69). Common adverse events included headache (32%), bone pain (33%), arthralgia (22%), and back pain (20%). Grade ≥ 3 adverse events occurred in 21% (95% CI: 0.09-0.41). Overall, luspatercept effectively reduced transfusion needs with an acceptable safety profile. Luspatercept significantly reduces transfusion burden in patients with β-thalassemia and demonstrates a manageable safety profile. These findings support luspatercept as an effective and well-tolerated therapeutic option that meaningfully reduces transfusion burden, potentially decreasing iron overload and improving quality of life for patients with β-thalassemia.
2026-04-27 | Dissecting polycomb complexes for enhanced fetal hemoglobin production.
Polycomb repressive complexes PRC1 and PRC2 regulate diverse developmental processes, including the fetal-to-adult switch in hemoglobin production, a process whose reversal is a goal for the treatment of sickle cell disease and β-thalassemia. PRC inhibitors show promise for various disorders, but use is limited because of pleiotropic PRC activities. We explored whether fetal hemoglobin (HbF) can be reactivated in adult erythroid cells by selective perturbations of PRC1 or PRC2 components without complete loss of PRC function. A high-density CRISPR-Cas9 mutagenesis screen identified a region in the EZH2 subunit where Cas9 induced exon 14 skipping (EZH2Δ14). EZH2Δ14, which lacks a portion of the CXC domain, relieves HbF repression while largely maintaining cellular fitness. EZH2Δ14 retains H3K27 methylation and repression of a PRC target gene subset. Experiments in cells derived from mice bearing human β-globin genes confirm that pathways mediating EZH2 control of HbF expression can function in a mouse model of HBG switching. These findings demonstrate that partial disruption of PRC can yield selective phenotypes, highlighting the therapeutic potential of targeting non-enzymatic domains within chromatin-modifying complexes.
2026-03-20 | Patient-Reported Outcomes With Luspatercept Through 5 Years of Treatment in Patients With Non-Transfusion-Dependent β-Thalassemia Treated in the BEYOND Trial.
In the phase 2, double-blind, randomized controlled BEYOND trial (NCT03342404), luspatercept increased hemoglobin levels in patients with non-transfusion-dependent β-thalassemia (NTDT). This study assessed long-term effects of luspatercept on patient-reported outcomes (PROs), using data from BEYOND and patients who continued luspatercept treatment in the phase 3b long-term follow-up (LTFU) study (NCT04064060). In BEYOND, patients received luspatercept or placebo Q3W for ≥ 48 weeks. PRO instruments included NTDT-PRO (BEYOND only), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), and 36-Item Short Form Survey (SF-36). Mixed-effects models with repeated measures estimated least squares mean changes from baseline in PROs. PROs were evaluable in 144 patients (luspatercept 95, placebo 49) from BEYOND and 58 (luspatercept) from LTFU. Luspatercept improved NTDT-PRO tiredness/weakness and shortness of breath domain, FACIT-F fatigue subscale, and SF-36 vitality scores versus placebo through double-blind treatment (generally maintained through week 96). In LTFU patients, significant, meaningful improvements from baseline in FACIT-F fatigue subscale and SF-36 vitality scores were observed within 12 weeks of treatment initiation and maintained for up to 5 years. Other FACIT-F and SF-36 domains improved or were maintained throughout LTFU. Luspatercept offers rapid and durable benefits by improving anemia-related symptoms and quality of life in patients with NTDT. Trial Registration: ClinicalTrials.gov Identifier: NCT03342404; NCT04064060.
cell therapies
2026-06-10 | CRISPR application in hematological disorders: from bench to bedside.
Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas genome editing has advanced from an experimental tool to a clinically validated therapeutic platform in hematology. Landmark successes in inherited blood diseases including sickle cell disease, β-thalassemia, and severe combined immunodeficiency, have demonstrated that precise and durable genetic modifications can be safely and effectively implemented in human hematopoietic cells, positioning hematology at the forefront of translational genome editing. Beyond monogenic disease, CRISPR-based approaches are transforming both the biological understanding and treatment of hematologic malignancies by enabling systematic interrogation of cancer dependencies, functional mapping of genetic vulnerabilities, and mechanism-driven target validation, including in vivo and immune-relevant contexts. In parallel, therapeutic applications are emerging through the development of engineered cellular therapies, including edited autologous and allogeneic immune effector cells designed to enhance antitumor efficacy, persistence, and immune evasion. This review synthesizes recent CRISPR-based advances across benign and malignant hematologic diseases. We compare major editing modalities, including nuclease-mediated disruption, base editing, prime editing, and CRISPR-based transcriptional modulation, and highlight key preclinical studies alongside emerging clinical trial data. We also discuss translational challenges that currently limit broader clinical adoption, including delivery and manufacturing scalability, off-target and genotoxicity risks, tumor and immune heterogeneity, and the long-term durability and fitness of edited cell populations. Finally, we outline priorities for the next phase of the field, emphasizing how continued innovation in CRISPR technologies may enable increasingly precise, durable, and mechanism-informed therapeutic strategies in hematology.
2026-06-08 | Correction of Ineffective Erythropoiesis and Normalization of Iron Homeostasis After Exagamglogene Autotemcel in Transfusion-Dependent β-Thalassemia.
Exagamglogene autotemcel (exa-cel) is a one-time, ex vivo, CRISPR-Cas9 gene edited cell therapy approved for patients with transfusion dependent β-thalassemia (TDT) aged 12-35 years. In a Phase 3 study (CLIMB THAL-111), exa-cel treatment resulted in reactivation of fetal hemoglobin and increases in total hemoglobin, leading to transfusion independence in 91% of participants. Here, we report on the impact of exa-cel treatment on measures of ineffective erythropoiesis and iron homeostasis, which were secondary and exploratory endpoints in CLIMB THAL-111 and the CLIMB-131 long-term follow-up study. Prior to exa-cel infusion, all participants were receiving regular red blood cell transfusions and iron chelation therapy. At time of data cut (April 2025), 98% of participants (55 of 56) had been transfusion independent for ≥ 12 months and 38 (68%) had discontinued iron removal therapy (mean duration off iron removal therapy 19.4 months). Following transfusion independence and cessation of iron removal therapy, erythroferrone concentrations decreased and hepcidin levels normalized in all participants, indicating correction of ineffective erythropoiesis and restoration of iron homeostasis. Further supporting this finding, improvements and trends toward normalization were seen in key erythropoiesis biomarkers, including erythropoietin levels, reticulocyte counts, and soluble transferrin receptor concentrations. Iron overload biomarkers, including ferritin, liver iron concentration, and cardiac T2*, decreased and then remained stable throughout follow-up, even after cessation of iron removal therapy. These results demonstrate restoration of effective erythropoiesis and iron homeostasis after exa-cel infusion in the setting of transfusion independence following reactivation of fetal hemoglobin. (CLIMB THAL-111 and CLIMB-131; Clinical Trials.gov numbers NCT03655678 and NCT04208529).
2026-06-05 | Comparative study of hemoglobin changes following transfusion of fresh and old blood in patients with thalassemia referred to Bahrami Hospital.
Thalassemia major is a severe hemoglobinopathy that requires blood transfusion; however, long term blood transfusion might increase morbidity and mortality. Hemoglobin (Hb) after transfusion determines the need for next transfusion. There is controversy regarding the effect of fresh packed RBC compared to old packed RBC transfusion on Hb. This study compared hemoglobin changes following transfusion between fresh and old packed RBC in transfusion-related thalassemia (TRT) patients. In this cohort study, 140 TRT patients (age > 5years) referred to Bahrami Children's Hospital in mid-2013 were included. Equal number (n = 70) of age and gender matched TRT patients with exposure to fresh (stored for less than 7 days) and old (stored for more than 7 days) packed RBC transfusion were followed for 14 days. In both groups, demographic information (age, sex) were recorded at enrolment. Physical examination data and blood parameters, including red blood cells (RBC), white blood cells (WBC), platelets (PLT), Hb, ferritin, transferrin, total iron binding capacity and bilirubin at baseline and follow up. Time-group interaction was significant only for WBC (p < 0.001) and Hb (p = 0.029) indicating that fresh packed RBC transfusion resulted in higher Hb and lower WBC at follow up compared to baseline levels. Among the baseline variables only fresh packed RBC transfusion was found to increase the odds of having Hb of at least 1 mg/dL higher than baseline (OR = 15.465, p < 0.001). Fresh packed RBC transfusion might increase the interval between transfusions due to more Hb elevation rate after transfusion in thalassemia major.
2026-06-02 | [Research Progress on the Bone Marrow Microenvironment in Beta-Thalassemia --Review].
Thalassemia is one of the most common and harmful single-gene recessive disorders in the clinic. It is characterized by impaired or absent production of one globin chain of hemoglobin in adults. The most common form is beta-thalassemia, which is associated with defects in the production of beta-globin chain, resulting in an imbalance in the ratio of alpha-globin to beta-globin. As a result, unbound free alpha-globin chains precipitated in red blood cell precursors, resulting in iron overload, ineffective red blood cell production, and changes in mesenchymal stem cells, osteoblasts, osteoclasts, and other associated cells. Among them, iron overload and ineffective red blood cell production will destroy the bone marrow microenvironment, which will cause further damage to the hematopoietic system. Therefore, the correction of the bone marrow microenvironment plays an important role in the treatment of thalassemia. This review summarizes studies on the destruction of the bone marrow microenvironment in beta-thalassemia, treatment options for improving the microenvironment and stem cell transplantation.
2026-05-05 | Genetic Engineering in Hematopoietic Stem Cells for β-Hemoglobinopathies Treatment: Advances, Challenges, and Clinical Translation.
β-hemoglobinopathies rank among the most prevalent inherited blood disorders globally. Traditional management strategies are primarily palliative and often associated with significant challenges, including iron overload and limited long-term efficacy. Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative option for transfusion-dependent patients, but its broader applicability is constrained by factors that limit its use. Utilizing viral vectors and gene-editing tools, particularly CRISPR-Cas9 technology, researchers have developed therapies that target the root causes of these disorders. These innovative approaches have demonstrated substantial therapeutic potential, accompanied by favorable safety profiles, in clinical settings. Since the initial investigations, the genome editing tool has rapidly advanced for genetic abnormalities, particularly monogenic blood diseases, including β-hemoglobinopathies. This method suggests an approach with lower concerns in viral gene integration and insertional mutagenesis issues. This review comprehensively surveys the therapeutic strategies for β-thalassemia and sickle cell disease (SCD) currently in preclinical and clinical development, with a focus on the evolving treatment paradigm. Looking forward, critical research priorities include optimizing the efficiency and specificity of gene-editing platforms and pioneering novel delivery systems to guarantee both therapeutic efficacy and clinical safety.
other
2026-06-12 | Cyclic Fevers in Pregnancy: A Case of Parvovirus-Related Hemophagocytic Lymphohistiocytosis.
Parvovirus B19 typically causes mild symptoms in healthy adults, including fever, rash, and arthralgias. Certain immunocompromised adult populations, including those with immunodeficiencies or hematologic disease, are at risk of clinically significant complications, including transient aplastic crisis. Further, in pregnant patients, there is a risk of transplacental viral transmission, which may lead to severe fetal anemia, nonimmune hydrops fetalis, and intrauterine fetal demise. The clinical course of parvovirus B19 in pregnant patients with underlying hematologic disease has not been well reported. In this case report, we present a 27-year-old pregnant patient with sickle cell beta thalassemia who was infected with parvovirus B19 at 20 weeks of gestation. She experienced a prolonged hospitalization characterized by persistent maternal vaso-occlusive crisis with concomitant transient aplastic crisis. There was suspected vertical transmission of the virus, leading to concern for severe fetal anemia and termination of the pregnancy. The patient continued to have cyclic fevers, bicytopenia, and a constellation of laboratory findings leading to a diagnosis of postviral hemophagocytic lymphohistiocytosis (HLH). She was successfully treated with pulse dose corticosteroids and an Interleukin-1 receptor antagonist with subsequent improvement of her symptoms and laboratory markers. This report highlights the distinct diagnostic and management challenges of parvovirus B19 in pregnant patients with comorbid hematologic disease, including a rare but serious sequela of the infection, and the risk for severe maternal and fetal complications.
2026-06-05 | Use of romosozumab for osteoporosis in β-thalassemia major.
Thalassemia bone disease is a common and severe complication of β-thalassemia major (TM), resulting from marrow expansion, hormonal deficiencies, including hypogonadism, iron toxicity, and increased bone turnover. These factors contribute to reduced BMD and increased susceptibility to minimal trauma fracture (MTF). Optimizing transfusions and iron chelation therapy, management of hormonal deficiencies, and antiresorptive therapies are the cornerstone of management. We report the use of romosozumab in 2 patients with TM and severe osteoporosis. This is the first case series describing the efficacy of romosozumab in the treatment of osteoporosis in patients with TM. After completion of 12 mo of monthly romosozumab, DXA scan demonstrated significant improvements in BMD despite previous prolonged exposure to antiresorptive therapy in both subjects. This represents a promising treatment option in patients with TM and osteoporosis.
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.
2026-04-09 | Mechanisms of resistance to Tmprss6 antisense oligonucleotides in a mouse model of β-thalassemia.
Non-transfusion dependent β-thalassemia (NTDT) is characterized by ineffective erythropoiesis, suppression of hepcidin, and iron overload, which is a major cause of morbidity and mortality. Hepatic protease Tmprss6 regulates hepcidin by modulating BMP/Smad signaling. Suppression of Tmprss6 in the mouse model of NTDT (Th3 mice), increased hepcidin and improved disease outcomes, but similar benefits have not been reported in human trials. We hypothesized that the resistance to the effects of anti-TMPRSS6 treatment in patients with NTDT may be caused by high erythroferrone (ERFE) concentrations and more severe iron overload, both known to modulate BMP/Smad signaling in hepatocytes. We therefore examined how ERFE and iron overload modulate the effects of Tmprss6 antisense oligonucleotides (ASO) in mouse models.We treated ERFE-overexpressing Th3 mice (T-E(M)) and their littermates (wild-type, Th3, and Erfe-overexpressing E(M) mice) with Tmprss6 ASO or non-targeting ASO for 4 weeks. Tmprss6 ASO increased phospho-Smad1/5/8 and hepcidin levels, decreased splenomegaly, reduced extramedullary erythropoiesis and improved iron parameters in Th3 mice but not in T-E(M) mice, despite similar Tmprss6 decrease. To determine whether iron overload alone blunted the effects of Tmprss6 ASO, we assessed the responses of C57BL/6 mice after 10 mg of iron dextran or 5000 ppm high iron diet. Unlike iron-adequate mice, iron-overloaded mice already had high phospho-Smad and hepcidin, with no further increase after Tmprss6 ASO treatment, and no effect on erythroid or iron parameters.Higher ERFE concentrations and more severe iron overload may be responsible for diminished benefits of Tmprss6 ASO in human NTDT.
2026-02-13 | miRNA-Mediated Regulation of γ-Globin to β-Globin Switching: Therapeutic Potential in β-Hemoglobinopathies.
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.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
29 orphan drug designations for Beta-thalassemia, including 7 approved therapies.
29 orphan drug designations for Beta-thalassemia, including 7 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
etavopivat | small molecules | FDA | 2025-03-21 | — | Novo Nordisk Inc. |
genetically modified CD34+ hematopoietic stem cells using a lentiviral vector carrying the beta A-T87Q-globin gene | gene therapies | FDA | 2024-07-11 | — | Kanglin Biotechnology (Hangzhou) Co., Ltd. |
Mitapivat sulfat [Pyrukynd] | small molecules | EMA | 2023-10-13 | 2026-05-22 | Agios Netherlands B.V. |
autologous CD34+ hematopoietic stem and progenitor cells edited by CRISPR/Cas12a ribonucleoprotein (RNP) at the HBG1 and HBG2 promoters | cell therapies | FDA | 2022-05-04 | — | Editas Medicine, Inc. |
synthetic 2?-O-(2-methoxyethyl)-modified antisense oligonucleotide linked to a tri-antennary cluster of N-acetyl galactosamine (GalNAc3) sugars targeting transmembrane protease, serine 6 messenger ribonucleic acid | oligonucleotides | FDA | 2020-10-15 | — | Ionis Pharmaceuticals, Inc. |
Synthetic double-stranded siRNA oligonucleotide directed against TMPRSS6 mRNA and covalently linked to a ligand containing 3 N-acetylgalactosamine residues | RNAs | FDA | 2020-06-26 | — | Silence Therapeutics GmbH |
6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3- tetrahydropyran-4-yl-7H-imidazo[1,5-a]pyrazin-8-one | small molecules | FDA | 2020-06-22 | — | IMARA, Inc. |
mitapivat [Aqvesme] | small molecules | FDA | 2020-06-08 | 2025-12-23 | Agios Pharmaceuticals, Inc. |
exagamglogene autotemcel [Casgevy] | combination | FDA | 2020-04-28 | 2024-01-16 | Vertex Pharmaceuticals Inc. |
Autologous CD34+ haematopoietic stem cells with a CRISPR-edited erythroid enhancer region of the BCL11A gene [Casgevy] | combination | EMA | 2019-10-17 | 2024-02-12 | Vertex Pharmaceuticals (Ireland) Limited |
2-(2-{[2-(1H-benzimidazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridine-2-yl)methyl]-1,3-oxazole-4-carboxamide trihydrochloride | small molecules | EMA | 2019-06-28 | — | Vifor France S.A. |
2-(2-{[2-(1H-benzimidazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide trihydrochloride | small molecules | FDA | 2019-06-17 | — | Vifor Pharma, Inc. |
autologous CD34+ hematopoietic stem and progenitor cells transfected with zinc finger nuclease messenger RNAs SB-mRENH1 and SB-mRENH2 | gene editing enzymes | FDA | 2019-06-04 | — | Sangamo Therapeutics, Inc. |
Divesiran | RNAs | EMA | 2019-01-11 | — | Silence Therapeutics GmbH |
hepcidin mimetic peptide | peptides | FDA | 2018-03-01 | — | Protagonist Therapeutics |
Bitopertin | small molecules | EMA | 2017-10-16 | — | Roche Registration GmbH |
bitopertin | small molecules | FDA | 2017-08-16 | — | Hoffmann-La Roche Inc. |
5-aza-2'-dexocytidine combined with 1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one | small molecules | FDA | 2017-02-16 | — | Novo Nordisk Inc. |
sirolimus | small molecules | FDA | 2016-06-21 | — | Rare Partners srl Impresa Sociale |
Sirolimus | small molecules | EMA | 2015-12-14 | — | Rare Partners srl Impresa Sociale |
Benserazide hydrochloride | small molecules | EMA | 2014-12-16 | — | Isabelle Ramirez |
Recombinant fusion protein consisting of a modified form of the extracellular domain of human activin receptor IIB linked to the human IgG1 Fc domain [Reblozyl] | proteins | EMA | 2014-07-29 | 2020-06-26 | Bristol-Myers Squibb Pharma EEIG |
betibeglogene autotemcel [Zynteglo] | cell therapies | FDA | 2013-03-18 | 2022-08-17 | Genetix Biotherapeutics Inc. |
Luspatercept-aamt [REBLOZYL] | proteins | FDA | 2013-03-11 | 2019-11-08 | Celgene Corporation |
Autologous haematopoietic stem cells transduced with lentiviral vector encoding the human beta-globin gene | gene therapies | EMA | 2009-04-29 | — | San Rocco Therapeutics Europe S.R.L. |
2 dimethylbutyrate | small molecules | FDA | 2008-06-18 | — | HemaQuest Pharmaceuticals, Inc. |
Lentiviral vector encoded with a human beta-globin gene plasmid | gene therapies | FDA | 2006-01-11 | — | San Rocco Therapeutics, LLC |
Isobutyramide | small molecules | FDA | 1992-12-18 | — | Perrine, Susan P., M.D. |
Arginine butyrate | small molecules | FDA | 1992-04-07 | — | Perrine, Susan P., M.D. |
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.