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
3,128 drug discovery papers about Beta-thalassemia, with 1 first-in-class and 13 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
3,128 drug discovery papers about Beta-thalassemia, with 1 first-in-class and 13 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-27 | Effect of HFE Gene H63D and S65C Mutations on the Severity of Secondary Iron Overload in Children With β-Thalassemia Major.
Coinheritance of HFE gene mutations in patients with β-thalassemia major (βTM) may further exacerbate systemic iron accumulation, potentially leading to earlier onset of iron-related complications. This study aimed to screen for HFE gene H63D and S65C mutations in children with βTM and evaluate their impact on the severity of secondary iron overload (IO). This cross-sectional study included 76 Sudanese children with βTM who were all receiving regular blood transfusions and iron chelation therapy. Polymerase chain reaction and Sanger DNA sequencing were used to screen for H63D and S65C mutations. IO severity was assessed by measuring serum ferritin (SF) levels using electrochemiluminescence immunoassay. The H63D mutation was identified in 17 (22.4%) of the thalassemic children; 16 (21.1%) were heterozygous, and one (1.3%) was homozygous. The S65C mutation was not present in any of the participants. SF levels were higher among carriers of the H63D variant allele (CG + GG) than among those with the wild-type allele (CC). Still, the difference was not statistically significant (median: 2051.0 vs. 1460.0 μg/L, p = 0.09). Furthermore, no statistically significant association was observed between the H63D mutation and the risk of myocardial iron loading (p = 0.087). The results revealed a statistically significant positive correlation between SF levels and the total number of blood transfusions (Spearman's ρ = 0.496, p < 0.001). A weak, positive, insignificant correlation was observed between SF levels and both the time since the last dose of iron chelation therapy (ρ = 0.257, p = 0.100) and C-reactive protein levels (ρ = 0.129, p = 0.267). The frequency of the HFE gene H63D mutation was relatively high among Sudanese children with βTM, whereas the S65C variant was absent. Although SF levels were higher in the carriers of the H63D variant allele compared to those with the wild-type allele, the difference was not statistically significant. These findings indicate limited clinical utility for routine screening for the HFE H63D and S65C mutations and emphasize the greater importance of optimizing transfusion and iron-chelating therapy practices to manage IO effectively.
2026-09-04 | Preclinical evaluation of entecavir as a fetal hemoglobin inducer using in vitro, in vivo, network pharmacology, and molecular docking approaches.
β-thalassemia is a group of hereditary, autosomal recessive blood disorders caused by reduced synthesis or absence of β-globin chains. Reactivation of hemoglobin F (Hb-F) by pharmacological means is an excellent remedial approach for treating β-thalassemia. Hydroxyurea is currently the only approved drug for Hb-F induction therapy. However, the variable efficacy and high cytotoxicity concerns of hydroxyurea have limited its utilization in clinical practices. This preclinical investigation demonstrated the potential of the antiviral drug entecavir (ETV) as an Hb-F inducer using the K562 cell line and validated in a β-YAC transgenic mice model. In the K562 cell line and β-YAC transgenic mice, the effects of ETV on Hb-F induction were investigated in a dose dependent manner. In mice the dose was given orally for 6 days/week for 4 weeks. A network pharmacology-based approach and molecular docking were also utilized to predict the target genes and the underlying mechanism of ETV in Hb-F induction. ETV in a dose dependent significantly increased the level of total haemoglobin, gamma-globin mRNA expression, and Hb-F production in the K562 cell line. In β-YAC mice, ETV confirmed gamma-globin gene expression at the mRNA and protein levels, as evidenced by increased haemoglobin F production in red blood cells. Furthermore, the docking analysis indicated that NFKB, PTGS2, HDAC2, and HIFIA are potential key targets of ETV, possibly involved in Hb-F induction, and must be validated experimentally. ETV, an approved drug for antiviral activity, increased the level of Hb-F in K562 cell line and in β-YAC transgenic mice, may suggest its use for the management of β-thalassemia. However, further research is required to test the drug's efficacy and the underlying gene targets in CD34+ erythroid progenitors of β-thalassemic patients.
2026-09-03 | ILF3 regulates erythroid differentiation: A single-cell transcriptomic analysis and cellular experiment.
Despite extensive knowledge of erythropoiesis, the role of interleukin enhancer binding factor 3 (ILF3) in β-thalassemia remains unclear. The aim of this study was to investigate the expression pattern and functional role of ILF3 during erythroid differentiation in β-thalassemia. (1) Single-cell transcriptomic profiles were constructed based on the GSE133181 dataset (3 healthy controls and 3 β-thalassemia patients). The differential expression of ILF3, transcriptional programs of erythroid subsets, pathway activity, and differentiation trajectory were analyzed. (2) ILF3 was knocked out in K562 cells using sgRNA. Cell proliferation was detected by CCK-8 assay, and apoptosis was measured by Annexin V-APC single staining. (1) ILF3 was downregulated in the β-thalassemia group, and the proportion of erythroid cells was significantly enriched in ILF3+ cells. (2) ILF3+ erythroid cells highly expressed maturation-related genes and were enriched in cell cycle and metabolic synthesis pathways, while ILF3- cells highly expressed stress-related genes and activated inflammatory stress pathways. (3) Trajectory analysis suggested early arrest of erythroid differentiation in β-thalassemia, with consistently low ILF3 expression throughout the disease group. (4) Knockout of ILF3 promoted apoptosis in K562 cells. ILF3 is downregulated in β-thalassemia, and its deficiency may contribute to erythroid differentiation arrest and ineffective hematopoiesis by inducing apoptosis and potentially enhancing inflammatory stress.
2026-08-28 | Brazilin reduces toxic iron species and oxidative damage in iron-loaded β-thalassemic mice.
Iron overload in β-thalassemia promotes the accumulation of redox-active iron species such as non-transferrin-bound iron (NTBI) and labile plasma iron (LPI), which cause oxidative stress and tissue damage. Brazilin, a natural phenolic compound from Caesalpinia sappan L., has antioxidant and iron-chelating properties. However, its role in protection against iron-related toxicity remains unclear. In this study, we investigated the effects of brazilin on iron overload and oxidative stress in iron-loaded β-thalassemia knockout (BKO) mice. Iron overload was induced with a 0.2% TMH-ferrocene diet, and mice were treated with deferiprone (DFP 50 mg/kg body weight) or brazilin (50 and 100 mg/kg body weight). Iron parameters, oxidative stress markers, iron-regulatory gene expression, and histopathological changes were evaluated. Iron-loaded BKO mice showed increased levels of NTBI, LPI, and non-heme iron in red blood cells, tissue iron accumulation, lipid peroxidation, and altered hepcidin (HAMP) and transferrin receptor (TfR) expression. Brazilin substantially reduced NTBI, LPI, hepatic iron accumulation, and malondialdehyde (MDA) levels, and increased glutathione levels in the plasma and liver. It also modulated HAMP and TfR expression, and histologically reduced hepatic iron deposition, although the reduction in cardiac iron levels was modest. These findings demonstrate that brazilin attenuates iron overload and associated oxidative stress in β-thalassemic mice, consistent with its iron-chelating and antioxidant properties, and support its potential as an adjunctive approach for managing iron overload in β-thalassemia.
2026-08-27 | Green Tea Extract Attenuates Oxidative Stress and Prolongs Red Blood Cell Survival in Iron-Overloaded β-Thalassemic Mice.
Green tea extract (GTE) contains catechin polyphenols with potent antioxidant and iron-chelating activities. This study investigated whether GTE could attenuate oxidative stress and improve red blood cell (RBC) survival in iron-overloaded β-thalassemic mice. Catechin composition and antioxidant activity of GTE and black tea extract (BTE) were evaluated using HPLC-photodiode array detection and ABTS radical scavenging assays. Anti-hemolytic effects were examined in RBC from healthy subjects and transfusion-dependent β-thalassemia patients. In vivo studies were performed using male C57BL/6J wild-type (WT) and heterozygous β-globin knockout (BKO) mice fed a ferrocene-enriched diet to induce iron overload. Mice subsequently received oral GTE (300 mg/kg/day) or deferiprone (DFP, 50 mg/kg/day) for 12 weeks. GTE contained markedly higher levels of catechin derivatives, particularly epigallocatechin-3-gallate, and exhibited stronger antioxidant activity than BTE. GTE significantly reduced RBC hemolysis, reactive oxygen species, malondialdehyde, and plasma non-transferrin-bound iron levels while restoring glutathione concentrations and prolonging RBC survival in iron-overloaded mice. The protective effects of GTE were comparable to DFP treatment. These findings suggest that GTE may serve as a promising natural adjunctive strategy for reducing oxidative injuries in β-thalassemia and iron-overload disorders.
gene therapies
2026-09-30 | Precision base-editing of the cryptic 3' acceptor site to correct the RNA splicing defect of β654-thalassemia.
β-Thalassemia is one of the most common inherited disorders worldwide and is caused by mutations affecting β-globin production. β654 mutation (IVS2-654, C > T) is one of the most frequently occurring β-thalassemia alleles in Han Chinese population, which activates a cryptic 3' splice site and leads to aberrant RNA splicing. Previous studies demonstrated that direct base editing of the IVS2-654 mutation is challenging because suitable single-guide RNAs (sgRNAs) cannot effectively target this site. Here we investigated an alternative therapeutic strategy by targeting the mutation-activated cryptic 3' splice acceptor site, rather than the disease-causing mutation itself. We first introduced base substitutions into the cryptic splice acceptor site in a β654-thalassemia mouse model using CRISPR-Cas9-mediated homology-directed repair, which restored normal RNA splicing and validated the therapeutic rationale of this approach. We then generated base-edited β654 mice by microinjecting Td-CBEmax mRNA together with sgRNAs targeting the cryptic splice acceptor site into one-cell embryos. Base editing was successfully achieved in 78% of live-born β654 mice, of which 86% produced correctly spliced β-globin transcripts. Restoration of normal RNA splicing was accompanied by marked improvement of hematological parameters and tissue pathology in most base-edited founder mice and their offspring compared with non-edited β654 mice. Together, these findings demonstrate that mutation-activated cryptic splice sites are therapeutically actionable targets for precision base editing and provide proof of concept for a precise and effective strategy to correct aberrant RNA splicing in β654-thalassemia.
2026-09-19 | Gene therapy for hereditary hematological disorders: From clinical breakthroughs to future horizons.
Hereditary hematological disorders, including sickle cell disease, β-thalassemia, and hemophilia, are severe monogenic diseases that impose substantial morbidity and lifelong treatment burdens. Conventional therapies are largely supportive and rarely curative, whereas gene therapy is increasingly transforming the therapeutic landscape by addressing the underlying genetic defects. This review summarizes the major gene therapy strategies currently being developed for hereditary hematological disorders, with a particular focus on gene addition, gene editing, and gene silencing, as well as ex vivo and in vivo delivery platforms. We highlight recent clinical breakthroughs, including approved products for hemoglobinopathies and hemophilia, and discuss emerging approaches such as base editing, prime editing, epigenetic modulation, and lipid nanoparticle-mediated delivery. In addition, we examine the major challenges that continue to limit broader clinical adoption, including immune responses, off-target effects, conditioning-related toxicity, manufacturing complexity, high cost, and limited accessibility. Finally, we outline future directions that may accelerate clinical translation, including improved editing precision, next-generation vector engineering, artificial intelligence-assisted design, scalable manufacturing, and more equitable access to treatment. Together, these advances suggest that gene therapy is steadily moving from experimental innovation toward durable, potentially curative treatment for hereditary hematological disorders.
2026-09-18 | CRISPR-Cas9 genome editing: technological advances, delivery strategies and precision engineering of primary cells for therapeutic application in genetic disorders and diabetes mellitus.
The CRISPR-Cas9 system has revolutionized modern life sciences, driving a paradigm shift in biomedical research and becoming an indispensable tool in molecular biology due to its remarkable precision, efficiency, and simplicity. Originating from a bacterial adaptive immune mechanism, CRISPR-Cas9 has evolved rapidly, providing a versatile framework for manipulating genetic material and addressing a wide spectrum of human diseases. Recent progress includes the discovery of novel Cas orthologs and the rational engineering of Cas9 variants to enhance editing fidelity, broaden target range, and minimize off-target effects. Structural and functional optimization of single-guide RNAs (sgRNAs) has further improved target binding affinity, stability, and Cas9-sgRNA complex formation, thereby increasing overall editing performance. The development of high-fidelity Cas9 derivatives and next-generation platforms such as base editors and prime editors has enabled precise single-nucleotide substitutions and small insertions or deletions without generating double-stranded DNA breaks. Advanced delivery systems-including viral vectors, lipid nanoparticles, and ribonucleoprotein electroporation-have facilitated efficient CRISPR-mediated editing across in vitro, ex vivo, and in vivo models. Remarkable therapeutic milestones have been achieved in treating monogenic disorders such as sickle cell disease, β-thalassemia, and cystic fibrosis, where long-term clinical benefits have been documented. Furthermore, CRISPR-Cas9 technology is redefining diabetes research by enabling precise modeling of disease mechanisms, uncovering molecular pathways involved in glucose homeostasis, and opening new avenues for cellular and gene-based therapies. This review highlights recent advances in CRISPR-Cas9-mediated genome editing, emphasizing breakthroughs in primary cell editing and the development of translational models for genetic diseases and diabetes mellitus.
2026-09-10 | Mapping the Management-to-Cure Transition in Thalassemia Research: Semantic Topic Modeling of 17,651 Publications Across Three Decades.
Thalassemia syndromes affect millions worldwide, with the highest prevalence in the Mediterranean basin, the Middle East, South Asia, and southern China. For decades, standard care relied on lifelong transfusion and iron chelation, a management paradigm that extended survival without offering a cure. The first curative option, allogeneic hematopoietic stem cell transplantation (HSCT), emerged in the early 1980s; the first gene-editing therapy, Casgevy, followed in 2023, marking the latest step in this trajectory. Yet the research landscape underlying the broader management-to-cure transition has not been systematically characterized. We applied BERTopic, a transformer-based semantic topic model, to 17,651 PubMed-indexed thalassemia abstracts spanning 1990-2026, tracking topic prevalence over 37 years and comparing trajectories across seven national research communities. The model independently identified a thematic structure that separated management-oriented research (iron chelation, cardiac monitoring, prenatal screening) from curative research (hematopoietic stem cell transplantation [HSCT], gene therapy); the crossover point occurred around 2020, three years before the first gene-editing approval. By 2025, curative topics accounted for 14% of publications, versus 9% for management topics. Country-level analysis revealed marked divergence: US research focused more heavily on gene therapy (10.0% vs. 4.1% in China), while Chinese research maintained a stronger HSCT focus (6.3% vs. 4.0% in the US). These findings chart the course of a major therapeutic transition and carry direct implications for research funding allocation, global strategies for equitable access to curative therapies, and computational literature surveillance to inform clinical guideline updates.
2026-09-07 | Clinical base editing for β-hemoglobinopathies across different genetic backgrounds.
β-Hemoglobinopathies are monogenic disorders. We previously applied a transformer base editor (tBE) to reactivate fetal hemoglobin (HbF) expression, and five Chinese transfusion-dependent β-thalassemia (TDT) patients achieved transfusion independence. However, the applicability of tBE to sickle cell disease (SCD) and genetically different TDT populations remained unknown. Here, we show a four-patient descriptive report from three trials, including one African SCD patient and three TDT patients carrying mutations common in South and Southeast Asia. All patients achieve hematopoietic recovery, and red blood cell transfusions are discontinued in all cases. After more than 12 months of follow-up, all patients show durable editing, sustained high-level pan-cellular HbF expression, and transfusion independence. No vaso-occlusive episodes occur in the SCD patient. No off-target mutations, malignancies, or deaths are observed. These initial results support the feasibility of applying tBE to treat SCD and the reported TDT genotypes, warranting broader evaluation across diverse populations. ClinicalTrials.gov identifiers are as follows: NCT06328764, NCT06065189, and NCT06565026.
proteins
2026-09-01 | Impact of luspatercept in beta-thalassemia major with alloimmunization: A case report
Patients with Beta (β)-thalassemia require regular blood transfusions. The presence of red blood cell (RBC) alloantibodies can complicate transfusion treatment. This can lead to delays in obtaining compatible blood, and in some case temporarily rendering blood transfusion impossible. We present a case demonstrating the successful adjunctive management of a patient with transfusion-dependent β-thalassemia complicated by RBC alloimmunization using a novel therapeutic agent. A 32-year-old Thai female with homozygous β-thalassemia was admitted to the Hospital of Tropical Diseases, Bangkok, with symptoms of anemia. Cross-matching studies revealed the presence of alloantibodies at admission. Treatment with luspatercept, a novel erythroid maturation agent, resulted in an increase in hemoglobin levels and an extension of the transfusion interval. The patient received four doses of luspatercept while awaiting antigen-compatible RBC units. Although luspatercept had no direct effect on RBC alloimmunization or existing alloantibodies, its ability to reduce transfusion requirements may decrease the need for subsequent RBC transfusions, and thereby reduce further antigen exposure. This may be particularly beneficial in patients with complex alloantibody profiles. This case highlights the potential role of luspatercept as adjunctive supportive therapy to delay transfusions requirements in patients with transfusion-dependent β-thalassemia complicated by RBC alloimmunization.
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.
cell therapies
2026-07-09 | Non-genotoxic transplantation and in vivo selection through epitope editing.
The short-term and long-term effects of genotoxic pre-transplant conditioning remain barriers to the broader application of haematopoietic stem/progenitor cell (HSPC) transplantation and gene therapies1-4. Although monoclonal antibodies targeting KIT have been proposed as alternatives to chemotherapy or radiotherapy5-7, their pharmacokinetics hinder clinical applications owing to the risk of depleting transplanted HSPCs. Here, to address this issue, we identified amino acid changes in the extracellular domain of KIT that disrupt the binding of two therapeutic monoclonal antibodies8,9, which impair stem cell factor (SCF)-mediated signalling without affecting KIT expression or functionality. We exploited adenine base editing10 or prime editing11 to efficiently introduce these mutations in HSPCs and combined them with the disruption of the BCL11A erythroid enhancer to promote expression of fetal haemoglobin (HbF)12,13, a therapeutic approach for several haemoglobinopathies. This strategy enables in vivo co-selection of gene-engineered cells to reach the threshold required to provide therapeutic benefit in patients affected by sickle cell disease and β-thalassaemia. We show progressive enrichment of KIT plus BCL11A multiplex-edited haematopoiesis under selective pressure with KIT monoclonal antibody, in vitro and in vivo. We report that extended treatment with anti-KIT regimens leads to superior in vivo enrichment while avoiding clonal selection, as assessed by a lentiviral barcoded library. Finally, by overcoming the limitations of monoclonal antibody pharmacokinetics, epitope editing enables novel haematopoietic replacement regimens that are not limited by on-target graft elimination, allowing prolonged immune-based conditioning that maximizes haematopoietic niche clearance without chemo-radiotherapy or monoclonal antibody wash-out.
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.
other
2026-07-17 | CD117 epitope-shielded hematopoietic stem cell transplantation with toxin-free conditioning and in vivo selection ameliorates a β-thalassemia model.
Clinical evidence demonstrates that ex vivo gene therapy and genome engineering of hematopoietic stem and progenitor cells (HSPCs) could represent one-time cures. However, while genome editing itself has become increasingly efficient and precise, the toxic conditioning required for hematopoietic stem cell transplantation remains a major barrier to broad clinical implementation of these otherwise curative therapies. In particular, the use of busulfan for myeloablative conditioning constitutes a major safety concern. While preclinical studies established CD117 as a promising target for antigen-specific therapy, clinical translation faced setbacks balancing efficacy and safety. To overcome current limitations, we generated a new CD117-blocking monoclonal antibody (CIM058) and demonstrate its potency to block wild-type HSPCs. To enable long-term blockade of host HSPCs even after transplantation, we used prime editing to engineer CIM058-resistant human CD34+ HSPCs. When combined, CIM058 and the epitope engineered CD34+ HSPCs ameliorated disease phenotype in a β-thalassemia model. Our results suggest that this approach may overcome the reliance on busulfan or other myeloablative conditioning regimens with their associated morbidities, and by enabling toxin-free conditioning and in vivo selection of edited cells, may facilitate clinical implementation of these highly valuable genetic therapies.
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.
small molecules
2026-09-27 | Effect of HFE Gene H63D and S65C Mutations on the Severity of Secondary Iron Overload in Children With β-Thalassemia Major.
Coinheritance of HFE gene mutations in patients with β-thalassemia major (βTM) may further exacerbate systemic iron accumulation, potentially leading to earlier onset of iron-related complications. This study aimed to screen for HFE gene H63D and S65C mutations in children with βTM and evaluate their impact on the severity of secondary iron overload (IO). This cross-sectional study included 76 Sudanese children with βTM who were all receiving regular blood transfusions and iron chelation therapy. Polymerase chain reaction and Sanger DNA sequencing were used to screen for H63D and S65C mutations. IO severity was assessed by measuring serum ferritin (SF) levels using electrochemiluminescence immunoassay. The H63D mutation was identified in 17 (22.4%) of the thalassemic children; 16 (21.1%) were heterozygous, and one (1.3%) was homozygous. The S65C mutation was not present in any of the participants. SF levels were higher among carriers of the H63D variant allele (CG + GG) than among those with the wild-type allele (CC). Still, the difference was not statistically significant (median: 2051.0 vs. 1460.0 μg/L, p = 0.09). Furthermore, no statistically significant association was observed between the H63D mutation and the risk of myocardial iron loading (p = 0.087). The results revealed a statistically significant positive correlation between SF levels and the total number of blood transfusions (Spearman's ρ = 0.496, p < 0.001). A weak, positive, insignificant correlation was observed between SF levels and both the time since the last dose of iron chelation therapy (ρ = 0.257, p = 0.100) and C-reactive protein levels (ρ = 0.129, p = 0.267). The frequency of the HFE gene H63D mutation was relatively high among Sudanese children with βTM, whereas the S65C variant was absent. Although SF levels were higher in the carriers of the H63D variant allele compared to those with the wild-type allele, the difference was not statistically significant. These findings indicate limited clinical utility for routine screening for the HFE H63D and S65C mutations and emphasize the greater importance of optimizing transfusion and iron-chelating therapy practices to manage IO effectively.
2026-09-04 | Preclinical evaluation of entecavir as a fetal hemoglobin inducer using in vitro, in vivo, network pharmacology, and molecular docking approaches.
β-thalassemia is a group of hereditary, autosomal recessive blood disorders caused by reduced synthesis or absence of β-globin chains. Reactivation of hemoglobin F (Hb-F) by pharmacological means is an excellent remedial approach for treating β-thalassemia. Hydroxyurea is currently the only approved drug for Hb-F induction therapy. However, the variable efficacy and high cytotoxicity concerns of hydroxyurea have limited its utilization in clinical practices. This preclinical investigation demonstrated the potential of the antiviral drug entecavir (ETV) as an Hb-F inducer using the K562 cell line and validated in a β-YAC transgenic mice model. In the K562 cell line and β-YAC transgenic mice, the effects of ETV on Hb-F induction were investigated in a dose dependent manner. In mice the dose was given orally for 6 days/week for 4 weeks. A network pharmacology-based approach and molecular docking were also utilized to predict the target genes and the underlying mechanism of ETV in Hb-F induction. ETV in a dose dependent significantly increased the level of total haemoglobin, gamma-globin mRNA expression, and Hb-F production in the K562 cell line. In β-YAC mice, ETV confirmed gamma-globin gene expression at the mRNA and protein levels, as evidenced by increased haemoglobin F production in red blood cells. Furthermore, the docking analysis indicated that NFKB, PTGS2, HDAC2, and HIFIA are potential key targets of ETV, possibly involved in Hb-F induction, and must be validated experimentally. ETV, an approved drug for antiviral activity, increased the level of Hb-F in K562 cell line and in β-YAC transgenic mice, may suggest its use for the management of β-thalassemia. However, further research is required to test the drug's efficacy and the underlying gene targets in CD34+ erythroid progenitors of β-thalassemic patients.
2026-09-03 | ILF3 regulates erythroid differentiation: A single-cell transcriptomic analysis and cellular experiment.
Despite extensive knowledge of erythropoiesis, the role of interleukin enhancer binding factor 3 (ILF3) in β-thalassemia remains unclear. The aim of this study was to investigate the expression pattern and functional role of ILF3 during erythroid differentiation in β-thalassemia. (1) Single-cell transcriptomic profiles were constructed based on the GSE133181 dataset (3 healthy controls and 3 β-thalassemia patients). The differential expression of ILF3, transcriptional programs of erythroid subsets, pathway activity, and differentiation trajectory were analyzed. (2) ILF3 was knocked out in K562 cells using sgRNA. Cell proliferation was detected by CCK-8 assay, and apoptosis was measured by Annexin V-APC single staining. (1) ILF3 was downregulated in the β-thalassemia group, and the proportion of erythroid cells was significantly enriched in ILF3+ cells. (2) ILF3+ erythroid cells highly expressed maturation-related genes and were enriched in cell cycle and metabolic synthesis pathways, while ILF3- cells highly expressed stress-related genes and activated inflammatory stress pathways. (3) Trajectory analysis suggested early arrest of erythroid differentiation in β-thalassemia, with consistently low ILF3 expression throughout the disease group. (4) Knockout of ILF3 promoted apoptosis in K562 cells. ILF3 is downregulated in β-thalassemia, and its deficiency may contribute to erythroid differentiation arrest and ineffective hematopoiesis by inducing apoptosis and potentially enhancing inflammatory stress.
2026-08-28 | Brazilin reduces toxic iron species and oxidative damage in iron-loaded β-thalassemic mice.
Iron overload in β-thalassemia promotes the accumulation of redox-active iron species such as non-transferrin-bound iron (NTBI) and labile plasma iron (LPI), which cause oxidative stress and tissue damage. Brazilin, a natural phenolic compound from Caesalpinia sappan L., has antioxidant and iron-chelating properties. However, its role in protection against iron-related toxicity remains unclear. In this study, we investigated the effects of brazilin on iron overload and oxidative stress in iron-loaded β-thalassemia knockout (BKO) mice. Iron overload was induced with a 0.2% TMH-ferrocene diet, and mice were treated with deferiprone (DFP 50 mg/kg body weight) or brazilin (50 and 100 mg/kg body weight). Iron parameters, oxidative stress markers, iron-regulatory gene expression, and histopathological changes were evaluated. Iron-loaded BKO mice showed increased levels of NTBI, LPI, and non-heme iron in red blood cells, tissue iron accumulation, lipid peroxidation, and altered hepcidin (HAMP) and transferrin receptor (TfR) expression. Brazilin substantially reduced NTBI, LPI, hepatic iron accumulation, and malondialdehyde (MDA) levels, and increased glutathione levels in the plasma and liver. It also modulated HAMP and TfR expression, and histologically reduced hepatic iron deposition, although the reduction in cardiac iron levels was modest. These findings demonstrate that brazilin attenuates iron overload and associated oxidative stress in β-thalassemic mice, consistent with its iron-chelating and antioxidant properties, and support its potential as an adjunctive approach for managing iron overload in β-thalassemia.
2026-08-27 | Green Tea Extract Attenuates Oxidative Stress and Prolongs Red Blood Cell Survival in Iron-Overloaded β-Thalassemic Mice.
Green tea extract (GTE) contains catechin polyphenols with potent antioxidant and iron-chelating activities. This study investigated whether GTE could attenuate oxidative stress and improve red blood cell (RBC) survival in iron-overloaded β-thalassemic mice. Catechin composition and antioxidant activity of GTE and black tea extract (BTE) were evaluated using HPLC-photodiode array detection and ABTS radical scavenging assays. Anti-hemolytic effects were examined in RBC from healthy subjects and transfusion-dependent β-thalassemia patients. In vivo studies were performed using male C57BL/6J wild-type (WT) and heterozygous β-globin knockout (BKO) mice fed a ferrocene-enriched diet to induce iron overload. Mice subsequently received oral GTE (300 mg/kg/day) or deferiprone (DFP, 50 mg/kg/day) for 12 weeks. GTE contained markedly higher levels of catechin derivatives, particularly epigallocatechin-3-gallate, and exhibited stronger antioxidant activity than BTE. GTE significantly reduced RBC hemolysis, reactive oxygen species, malondialdehyde, and plasma non-transferrin-bound iron levels while restoring glutathione concentrations and prolonging RBC survival in iron-overloaded mice. The protective effects of GTE were comparable to DFP treatment. These findings suggest that GTE may serve as a promising natural adjunctive strategy for reducing oxidative injuries in β-thalassemia and iron-overload disorders.
gene therapies
2026-09-30 | Precision base-editing of the cryptic 3' acceptor site to correct the RNA splicing defect of β654-thalassemia.
β-Thalassemia is one of the most common inherited disorders worldwide and is caused by mutations affecting β-globin production. β654 mutation (IVS2-654, C > T) is one of the most frequently occurring β-thalassemia alleles in Han Chinese population, which activates a cryptic 3' splice site and leads to aberrant RNA splicing. Previous studies demonstrated that direct base editing of the IVS2-654 mutation is challenging because suitable single-guide RNAs (sgRNAs) cannot effectively target this site. Here we investigated an alternative therapeutic strategy by targeting the mutation-activated cryptic 3' splice acceptor site, rather than the disease-causing mutation itself. We first introduced base substitutions into the cryptic splice acceptor site in a β654-thalassemia mouse model using CRISPR-Cas9-mediated homology-directed repair, which restored normal RNA splicing and validated the therapeutic rationale of this approach. We then generated base-edited β654 mice by microinjecting Td-CBEmax mRNA together with sgRNAs targeting the cryptic splice acceptor site into one-cell embryos. Base editing was successfully achieved in 78% of live-born β654 mice, of which 86% produced correctly spliced β-globin transcripts. Restoration of normal RNA splicing was accompanied by marked improvement of hematological parameters and tissue pathology in most base-edited founder mice and their offspring compared with non-edited β654 mice. Together, these findings demonstrate that mutation-activated cryptic splice sites are therapeutically actionable targets for precision base editing and provide proof of concept for a precise and effective strategy to correct aberrant RNA splicing in β654-thalassemia.
2026-09-19 | Gene therapy for hereditary hematological disorders: From clinical breakthroughs to future horizons.
Hereditary hematological disorders, including sickle cell disease, β-thalassemia, and hemophilia, are severe monogenic diseases that impose substantial morbidity and lifelong treatment burdens. Conventional therapies are largely supportive and rarely curative, whereas gene therapy is increasingly transforming the therapeutic landscape by addressing the underlying genetic defects. This review summarizes the major gene therapy strategies currently being developed for hereditary hematological disorders, with a particular focus on gene addition, gene editing, and gene silencing, as well as ex vivo and in vivo delivery platforms. We highlight recent clinical breakthroughs, including approved products for hemoglobinopathies and hemophilia, and discuss emerging approaches such as base editing, prime editing, epigenetic modulation, and lipid nanoparticle-mediated delivery. In addition, we examine the major challenges that continue to limit broader clinical adoption, including immune responses, off-target effects, conditioning-related toxicity, manufacturing complexity, high cost, and limited accessibility. Finally, we outline future directions that may accelerate clinical translation, including improved editing precision, next-generation vector engineering, artificial intelligence-assisted design, scalable manufacturing, and more equitable access to treatment. Together, these advances suggest that gene therapy is steadily moving from experimental innovation toward durable, potentially curative treatment for hereditary hematological disorders.
2026-09-18 | CRISPR-Cas9 genome editing: technological advances, delivery strategies and precision engineering of primary cells for therapeutic application in genetic disorders and diabetes mellitus.
The CRISPR-Cas9 system has revolutionized modern life sciences, driving a paradigm shift in biomedical research and becoming an indispensable tool in molecular biology due to its remarkable precision, efficiency, and simplicity. Originating from a bacterial adaptive immune mechanism, CRISPR-Cas9 has evolved rapidly, providing a versatile framework for manipulating genetic material and addressing a wide spectrum of human diseases. Recent progress includes the discovery of novel Cas orthologs and the rational engineering of Cas9 variants to enhance editing fidelity, broaden target range, and minimize off-target effects. Structural and functional optimization of single-guide RNAs (sgRNAs) has further improved target binding affinity, stability, and Cas9-sgRNA complex formation, thereby increasing overall editing performance. The development of high-fidelity Cas9 derivatives and next-generation platforms such as base editors and prime editors has enabled precise single-nucleotide substitutions and small insertions or deletions without generating double-stranded DNA breaks. Advanced delivery systems-including viral vectors, lipid nanoparticles, and ribonucleoprotein electroporation-have facilitated efficient CRISPR-mediated editing across in vitro, ex vivo, and in vivo models. Remarkable therapeutic milestones have been achieved in treating monogenic disorders such as sickle cell disease, β-thalassemia, and cystic fibrosis, where long-term clinical benefits have been documented. Furthermore, CRISPR-Cas9 technology is redefining diabetes research by enabling precise modeling of disease mechanisms, uncovering molecular pathways involved in glucose homeostasis, and opening new avenues for cellular and gene-based therapies. This review highlights recent advances in CRISPR-Cas9-mediated genome editing, emphasizing breakthroughs in primary cell editing and the development of translational models for genetic diseases and diabetes mellitus.
2026-09-10 | Mapping the Management-to-Cure Transition in Thalassemia Research: Semantic Topic Modeling of 17,651 Publications Across Three Decades.
Thalassemia syndromes affect millions worldwide, with the highest prevalence in the Mediterranean basin, the Middle East, South Asia, and southern China. For decades, standard care relied on lifelong transfusion and iron chelation, a management paradigm that extended survival without offering a cure. The first curative option, allogeneic hematopoietic stem cell transplantation (HSCT), emerged in the early 1980s; the first gene-editing therapy, Casgevy, followed in 2023, marking the latest step in this trajectory. Yet the research landscape underlying the broader management-to-cure transition has not been systematically characterized. We applied BERTopic, a transformer-based semantic topic model, to 17,651 PubMed-indexed thalassemia abstracts spanning 1990-2026, tracking topic prevalence over 37 years and comparing trajectories across seven national research communities. The model independently identified a thematic structure that separated management-oriented research (iron chelation, cardiac monitoring, prenatal screening) from curative research (hematopoietic stem cell transplantation [HSCT], gene therapy); the crossover point occurred around 2020, three years before the first gene-editing approval. By 2025, curative topics accounted for 14% of publications, versus 9% for management topics. Country-level analysis revealed marked divergence: US research focused more heavily on gene therapy (10.0% vs. 4.1% in China), while Chinese research maintained a stronger HSCT focus (6.3% vs. 4.0% in the US). These findings chart the course of a major therapeutic transition and carry direct implications for research funding allocation, global strategies for equitable access to curative therapies, and computational literature surveillance to inform clinical guideline updates.
2026-09-07 | Clinical base editing for β-hemoglobinopathies across different genetic backgrounds.
β-Hemoglobinopathies are monogenic disorders. We previously applied a transformer base editor (tBE) to reactivate fetal hemoglobin (HbF) expression, and five Chinese transfusion-dependent β-thalassemia (TDT) patients achieved transfusion independence. However, the applicability of tBE to sickle cell disease (SCD) and genetically different TDT populations remained unknown. Here, we show a four-patient descriptive report from three trials, including one African SCD patient and three TDT patients carrying mutations common in South and Southeast Asia. All patients achieve hematopoietic recovery, and red blood cell transfusions are discontinued in all cases. After more than 12 months of follow-up, all patients show durable editing, sustained high-level pan-cellular HbF expression, and transfusion independence. No vaso-occlusive episodes occur in the SCD patient. No off-target mutations, malignancies, or deaths are observed. These initial results support the feasibility of applying tBE to treat SCD and the reported TDT genotypes, warranting broader evaluation across diverse populations. ClinicalTrials.gov identifiers are as follows: NCT06328764, NCT06065189, and NCT06565026.
proteins
2026-09-01 | Impact of luspatercept in beta-thalassemia major with alloimmunization: A case report
Patients with Beta (β)-thalassemia require regular blood transfusions. The presence of red blood cell (RBC) alloantibodies can complicate transfusion treatment. This can lead to delays in obtaining compatible blood, and in some case temporarily rendering blood transfusion impossible. We present a case demonstrating the successful adjunctive management of a patient with transfusion-dependent β-thalassemia complicated by RBC alloimmunization using a novel therapeutic agent. A 32-year-old Thai female with homozygous β-thalassemia was admitted to the Hospital of Tropical Diseases, Bangkok, with symptoms of anemia. Cross-matching studies revealed the presence of alloantibodies at admission. Treatment with luspatercept, a novel erythroid maturation agent, resulted in an increase in hemoglobin levels and an extension of the transfusion interval. The patient received four doses of luspatercept while awaiting antigen-compatible RBC units. Although luspatercept had no direct effect on RBC alloimmunization or existing alloantibodies, its ability to reduce transfusion requirements may decrease the need for subsequent RBC transfusions, and thereby reduce further antigen exposure. This may be particularly beneficial in patients with complex alloantibody profiles. This case highlights the potential role of luspatercept as adjunctive supportive therapy to delay transfusions requirements in patients with transfusion-dependent β-thalassemia complicated by RBC alloimmunization.
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.
cell therapies
2026-07-09 | Non-genotoxic transplantation and in vivo selection through epitope editing.
The short-term and long-term effects of genotoxic pre-transplant conditioning remain barriers to the broader application of haematopoietic stem/progenitor cell (HSPC) transplantation and gene therapies1-4. Although monoclonal antibodies targeting KIT have been proposed as alternatives to chemotherapy or radiotherapy5-7, their pharmacokinetics hinder clinical applications owing to the risk of depleting transplanted HSPCs. Here, to address this issue, we identified amino acid changes in the extracellular domain of KIT that disrupt the binding of two therapeutic monoclonal antibodies8,9, which impair stem cell factor (SCF)-mediated signalling without affecting KIT expression or functionality. We exploited adenine base editing10 or prime editing11 to efficiently introduce these mutations in HSPCs and combined them with the disruption of the BCL11A erythroid enhancer to promote expression of fetal haemoglobin (HbF)12,13, a therapeutic approach for several haemoglobinopathies. This strategy enables in vivo co-selection of gene-engineered cells to reach the threshold required to provide therapeutic benefit in patients affected by sickle cell disease and β-thalassaemia. We show progressive enrichment of KIT plus BCL11A multiplex-edited haematopoiesis under selective pressure with KIT monoclonal antibody, in vitro and in vivo. We report that extended treatment with anti-KIT regimens leads to superior in vivo enrichment while avoiding clonal selection, as assessed by a lentiviral barcoded library. Finally, by overcoming the limitations of monoclonal antibody pharmacokinetics, epitope editing enables novel haematopoietic replacement regimens that are not limited by on-target graft elimination, allowing prolonged immune-based conditioning that maximizes haematopoietic niche clearance without chemo-radiotherapy or monoclonal antibody wash-out.
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.
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2026-07-17 | CD117 epitope-shielded hematopoietic stem cell transplantation with toxin-free conditioning and in vivo selection ameliorates a β-thalassemia model.
Clinical evidence demonstrates that ex vivo gene therapy and genome engineering of hematopoietic stem and progenitor cells (HSPCs) could represent one-time cures. However, while genome editing itself has become increasingly efficient and precise, the toxic conditioning required for hematopoietic stem cell transplantation remains a major barrier to broad clinical implementation of these otherwise curative therapies. In particular, the use of busulfan for myeloablative conditioning constitutes a major safety concern. While preclinical studies established CD117 as a promising target for antigen-specific therapy, clinical translation faced setbacks balancing efficacy and safety. To overcome current limitations, we generated a new CD117-blocking monoclonal antibody (CIM058) and demonstrate its potency to block wild-type HSPCs. To enable long-term blockade of host HSPCs even after transplantation, we used prime editing to engineer CIM058-resistant human CD34+ HSPCs. When combined, CIM058 and the epitope engineered CD34+ HSPCs ameliorated disease phenotype in a β-thalassemia model. Our results suggest that this approach may overcome the reliance on busulfan or other myeloablative conditioning regimens with their associated morbidities, and by enabling toxin-free conditioning and in vivo selection of edited cells, may facilitate clinical implementation of these highly valuable genetic therapies.
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.
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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 | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
etavopivat | small molecules | FDA | Novo Nordisk Inc. | |
genetically modified CD34+ hematopoietic stem cells using a lentiviral vector carrying the beta A-T87Q-globin gene | gene therapies | FDA | — | Kanglin Biotechnology (Hangzhou) Co., Ltd. |
Mitapivat sulfat [Pyrukynd] | small molecules | EMA | Approved | 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 | 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 | 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 | 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 | IMARA, Inc. | |
mitapivat [Aqvesme] | small molecules | FDA | Approved | Agios Pharmaceuticals, Inc. |
exagamglogene autotemcel [Casgevy] | combination | FDA | Approved | Vertex Pharmaceuticals Inc. |
Autologous CD34+ haematopoietic stem cells with a CRISPR-edited erythroid enhancer region of the BCL11A gene [Casgevy] | combination | EMA | Approved | 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 | 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 | 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 | Sangamo Therapeutics, Inc. | |
Divesiran | RNAs | EMA | Silence Therapeutics GmbH | |
hepcidin mimetic peptide | peptides | FDA | Protagonist Therapeutics | |
Bitopertin | small molecules | EMA | Roche Registration GmbH | |
bitopertin | small molecules | FDA | 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 | — | Novo Nordisk Inc. |
sirolimus | small molecules | FDA | Rare Partners srl Impresa Sociale | |
Sirolimus | small molecules | EMA | Rare Partners srl Impresa Sociale | |
Benserazide hydrochloride | small molecules | EMA | 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 | Approved | Bristol-Myers Squibb Pharma EEIG |
betibeglogene autotemcel [Zynteglo] | cell therapies | FDA | Approved | Genetix Biotherapeutics Inc. |
Luspatercept-aamt [REBLOZYL] | proteins | FDA | Approved | Celgene Corporation |
Autologous haematopoietic stem cells transduced with lentiviral vector encoding the human beta-globin gene | gene therapies | EMA | San Rocco Therapeutics Europe S.R.L. | |
2 dimethylbutyrate | small molecules | FDA | HemaQuest Pharmaceuticals, Inc. | |
Lentiviral vector encoded with a human beta-globin gene plasmid | gene therapies | FDA | — | San Rocco Therapeutics, LLC |
Isobutyramide | small molecules | FDA | — | Perrine, Susan P., M.D. |
Arginine butyrate | small molecules | FDA | Perrine, Susan P., M.D. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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