bims-conane 2026-06-07 papers

Blood Adv. 2026 Jun 04. pii: bloodadvances.2026019799. [Epub ahead of print]

Phase 2a randomized study to evaluate sapablursen in patients with non-transfusion dependent β-thalassemia intermedia.

Ali Taher, Michael D Diamantidis, Antonis Kattamis, Yesim Aydinok, Zane Samuel Kaplan, Andy Dibble, Steve Dorow, Shane Doherty, Joel Mathews, Shiangtung Jung, Y Paul Goldberg, Joseph Tami, Sanjay Bhanot, Eugene Schneider, Brett P Monia, Terrance D Barrett.

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.

DOI: https://doi.org/10.1182/bloodadvances.2026019799

Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2026 Apr;34(2): 617-620

[Research Progress on the Bone Marrow Microenvironment in Beta-Thalassemia --Review].

Xin Peng, Ya-Jie Wang, Zeng-Zheng Li, Jun-Xue Ni.

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.

Keywords: beta-thalassemia; bone marrow microenvironment; stem cell transplantation; extracellular vesicle; traditional Chinese medicine treatment

DOI: https://doi.org/10.19746/j.cnki.issn1009-2137.2026.02.048

Cureus. 2026 May;18(5): e108227

Late Recognition of Glucose-6-Phosphate Dehydrogenase Deficiency in a 70-Year-Old Man: A Case Report.

Julie Huynh, Lauren Eisenbud, Rodolfo Gutierrez, Fukai L Chuang, Daniel Dichter.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymatic disorder of red blood cells worldwide and typically presents in childhood or early adulthood following exposure to oxidative stressors. Late-life diagnosis is uncommon and may be overlooked in patients without exposure to classic hemolytic triggers. We report the case of a 70-year-old man with intermittent, mild macrocytic anemia who was ultimately diagnosed with G6PD deficiency. This case highlights how G6PD deficiency may remain clinically silent for decades, discusses reasons for delayed diagnosis, and emphasizes the importance of considering inherited hemolytic disorders in older adults with unexplained macrocytic anemia.

Keywords: acute hemolytic anemia; fava beans; glucose-6-phosphate-dehydrogenase deficiency (g6pd); macrocytosis; sulfa drug

DOI: https://doi.org/10.7759/cureus.108227

J Clin Lab Anal. 2026 Jun 02. e70272

Beta-Thalassemia in Spain: Results From the National Thalassemia Registry and Molecular Analysis of Patients With Transfusion-Dependent Thalassemia.

BACKGROUND: Beta-thalassemia is a genetically heterogeneous hemoglobinopathy with marked clinical variability. In Spain, comprehensive nationwide data on transfusion-dependent beta-thalassemia (TDT) remain limited, particularly regarding molecular characterization.
METHODS: This observational study analyzed data from the National Thalassemia Registry of the Spanish Society of Hematology and Hemotherapy (SEHH). Between November 2022 and February 2025, 147 patients with beta-thalassemia from 42 hospitals were registered; this report focuses on 78 patients with TDT. Clinical, transfusion, and biochemical data were collected, and molecular analysis of the HBB and HBA genes was performed using Sanger sequencing, next-generation sequencing, and complementary techniques. Genotypes were classified according to the degree of beta-globin synthesis reduction.
RESULTS: The mean age of TDT patients was 34.3 years, and 73.1% were of Spanish origin. Patients received a mean of 31.4 packed red blood cell units per year. Splenectomy had been performed in 35.9% of cases. Most patients showed adequate iron overload control, with median serum ferritin levels below 1000 ng/mL. Twenty-four different HBB mutations were identified; the most frequent were CD39 (C > T), IVS-1-nt1 (G > A), IVS-1-nt110 (G > A), IVS-1-nt6 (T > C), and IVS-1-nt1 (G > T), accounting for 75% of alleles. Genotype distribution was 55.2% β0/β0, 30.3% β0/β+, and 14.4% β+/β+. Patients with β+/β+ genotypes had significantly lower ferritin levels.
CONCLUSIONS: This nationwide registry highlights the genetic and clinical heterogeneity of TDT in Spain and underscores the value of molecular characterization for patient management, genetic counseling, and future therapeutic strategies.

Keywords: HBB mutations; beta‐thalassemia; molecular genetics; national registry; transfusion‐dependent thalassemia

DOI: https://doi.org/10.1002/jcla.70272

Blood Adv. 2026 Jun 04. pii: bloodadvances.2025019368. [Epub ahead of print]

Real-world safety profile of twice a day deferiprone in patients with thalassemia, sickle cell disease, or other anemias.

Sujit Sheth, Ashutosh Lal, Abena Appiah-Kubi, Scott A Peslak, Noemi Toiber Temin, Mengru Amanda Chen, Thomas D Coates.

Iron overload is a significant cause of transfusion-related morbidity and mortality. Deferiprone (DFP) is an established oral iron chelator approved for the treatment of transfusional iron overload in patients with thalassemia, sickle cell disease (SCD), or other anemias. Initially approved as a three times-a-day (TID) formulation, a twice-a-day (BID) formulation was developed to improve patient adherence. Here, we assess the safety of DFP BID in patients with thalassemia, SCD, or other anemias in real-world clinical practice in the United States. Data for patients referred for DFP BID between July 1, 2020 to August 31, 2023 were obtained from the Ferriprox® Total Care Registry. The frequency of adverse events (AEs), serious AEs (SAEs), AEs of special interest and fatal outcomes was assessed. Of the 425 patients referred to the registry, 348 received ≥one DFP shipment and had a primary diagnosis of thalassemia syndromes (N=129), SCD (N=189), or other anemias (N=30) (safety analysis group). Mean (SD) DFP exposure was 343.0 (281.9) days. In total, 1021 AEs and 369 SAEs were reported. As seen with the TID formulation, the most common adverse events with DFP BID were predominantly gastrointestinal or related to underlying disease. Cases of neutropenia and agranulocytosis were rare, reported in 1.7% and 0.6% of patients, respectively and all recovered. None of the 26 fatal outcomes reported were assessed as related to DFP treatment. DFP BID was well-tolerated in real-world clinical practice, and the safety profile was consistent with DFP TID. No new safety concerns were observed.

DOI: https://doi.org/10.1182/bloodadvances.2025019368

FEBS J. 2026 Jun 01.

A quantitative dissection of the DNA-binding properties of pathogenic GATA1 mutants.

Kaoru Takasaki.

Transcription factors are modulated by a precisely coordinated set of conditions, including cell context, target sequences and their accessibility, and co-factor recruitment. Disruption to any of these conditions can dramatically affect transcription factor activity, but quantitatively characterizing the consequences of individual mutations-either in the transcription factors themselves or in their target sequences-has remained a technical challenge. Zambo et al. present an innovation on their native holdup assay that measures DNA-protein binding activity under physiologic or near-physiologic conditions and use mutant GATA1-ATP2B4 binding as an illustrative example. This technique holds promise for uncovering the molecular mechanisms underlying genetically-driven diseases.

Keywords: DNA–protein binding; GATA1; GATA1s; erythropoiesis; native holdup assay

DOI: https://doi.org/10.1111/febs.70614

Front Pediatr. 2026 ;14 1790301

Case Report: Atypical hepatobiliary manifestations associated with erythrocyte membrane instability in glucose transporter type 1 deficiency syndrome.

Hahnbie Lee, Sook Won Ryu, Jeana Hong.

Background: Glucose transporter type 1 (GLUT1) deficiency syndrome (GLUT1DS) is a rare neurometabolic disorder caused by pathogenic variants in SLC2A1. While neurological symptoms such as early-onset epilepsy, developmental delay, and movement disorders are well documented, hematologic and hepatobiliary complications are rarely reported, and their underlying mechanisms remain poorly defined.
Case presentation: We report a boy diagnosed with GLUT1DS at five years of age who presented with intractable seizures and persistent indirect hyperbilirubinemia. Genetic testing identified a heterozygous in-frame deletion in SLC2A1 [c.1306_1308del (p.Ile436del)], confirming the diagnosis of GLUT1DS. A co-occurring heterozygous UGT1A1 variants including coding and promoter lesions were also identified, initially suggestive of impaired bilirubin conjugation. During follow-up, the patient developed recurrent episodes of jaundice, anemia, and abdominal pain, ultimately attributed to chronic hemolysis with gallstone-related cholestasis requiring endoscopic retrograde cholangiopancreatography. To assess erythrocyte membrane integrity, specialized red blood cell studies were performed at 11 years of age. A temperature-dependent potassium leak test demonstrated cold-enhanced cation leakage consistent with pseudohyperkalemia and cryohydrocytosis, providing functional evidence of erythrocyte membrane instability associated with GLUT1 dysfunction.
Conclusion: This case expands the phenotypic spectrum of GLUT1DS by linking erythrocyte membrane instability to recurrent hemolysis and rarely reported hepatobiliary complications. Functional evaluation of erythrocyte membrane integrity may facilitate recognition of atypical systemic manifestations of GLUT1DS and supports the need for multidisciplinary surveillance beyond neurological care.

Keywords: GLUT1 deficiency syndrome; cryohydrocytosis; gallstones; glucose transporter type 1; hemolysis

DOI: https://doi.org/10.3389/fped.2026.1790301