bims-conane 2025-11-30 papers

Orphanet J Rare Dis. 2025 Nov 25.

Revisiting hemoglobin constant spring: molecular insights, pathophysiological mechanisms, and clinical perspectives.

Narawich Wongkhammul, Pinyaphat Khamphikham, Supawadee Maneekesorn, Pimlak Charoenkwan.

Keywords: HBA2 gene; Alpha-thalassemia; Gene therapy; Genotype-phenotype correlation; Hemoglobin constant spring; Molecular basis; Termination codon mutation

DOI: https://doi.org/10.1186/s13023-025-04120-5

Orphanet J Rare Dis. 2025 Nov 25.

Cerebrovascular involvement in hereditary spherocytosis: observational cohort and case-control MRI study.

Renzo Manara, Marcella Contieri, Giovanni Librizzi, Teresa Palma, Saverio Scianguetta, Carmine Perna, Annalisa Valentina Villani, Sofia Maria Rosaria Matarese, Margherita Luciano, Alessia Amodio, Maria Agnese Pirozzi, Raffaella Colombatti, Claudia Santoro, Mario Cirillo, Francesco di Salle, Fabrizio Esposito, Silverio Perrotta, Immacolata Tartaglione.

Keywords: Brain MRI and MR-Angiography; Cerebrovascular disease; Hereditary spherocytosis; Moyamoya syndrome

DOI: https://doi.org/10.1186/s13023-025-04121-4

Orphanet J Rare Dis. 2025 Nov 25. 20(1): 608

Safety and pharmacodynamics of the ferroportin inhibitor vamifeport in patients with non-transfusion-dependent β-thalassemia: results from a randomized phase 2a study.

Antonis Kattamis, Ali Taher, Vip Viprakasit, Carina Levin, Ricardo Hermosilla, Peter Szecsödy, Frank Richard, M Domenica Cappellini, John Porter.

BACKGROUND: Non-transfusion-dependent beta-thalassemia (β-NTDT) is characterized by ineffective erythropoiesis, increased intestinal iron absorption, and iron overload. The ferroportin inhibitor, vamifeport, has been shown to improve erythropoiesis via decreases in serum iron and transferrin saturation levels in preclinical models and healthy volunteer studies.
OBJECTIVE: The objective of this 12-week, double-blind, randomized, placebo-controlled, phase 2a study was to assess the safety and tolerability of vamifeport versus placebo in adults with β-NTDT (primary endpoint). Iron-related pharmacodynamic effects (preliminary efficacy) were also assessed as a secondary endpoint.
METHODS: Randomized, adult patients weighing 40-59 kg and 60-100 kg received vamifeport 60 mg and 120 mg (once [QD] or twice [BID] daily), respectively, for 12 weeks. Non-transfusion-dependent thalassemia was defined as transfusion requirements < 5 units of red blood cells during the 24 weeks before randomization.
RESULTS: Twenty-five patients were included (vamifeport QD n = 9, BID n = 12; placebo n = 4); 64% were male and 56% weighed < 60 kg. Baseline serum iron and transferrin saturation levels were similar across treatment groups. All treatment-emergent adverse events were mild/moderate, and rates were similar across groups (vamifeport QD 67%, BID 58%; placebo 75%). There were no deaths or serious treatment-emergent adverse events and no clinically relevant changes in safety parameters. Serum iron and transferrin saturation levels decreased by 2 h after the first vamifeport dose (mean [standard deviation] decreased QD - 12.2 [6.5], BID - 14.5 [12.1] µmol/L and QD - 33.6 [18.9], BID - 37.2 [27.6] %, respectively) and remained below baseline levels at each subsequent visit. There were no clinically meaningful changes in the placebo group.
CONCLUSION: In this 12-week study, vamifeport had a favorable safety/tolerability profile, with no changes in hemoglobin levels ≥ 1.0 g/dL, and promising pharmacodynamic effects versus placebo in adults with β-NTDT.
TRIAL REGISTRATION: ClinicalTrials.gov, NCT04364269. Registered 01 April 2020; Prospectively registered, https://clinicaltrials.gov/study/NCT04364269?term=NCT04364269&rank=1 .

Keywords: Iron; Tolerability; Transferrin saturation; Vamifeport; Β-thalassemia

DOI: https://doi.org/10.1186/s13023-025-04119-y

Sci Transl Med. 2025 Nov 26. 17(826): eadt8617

Base editing of β0-thalassemia mutations as a therapeutic strategy for severe β-hemoglobinopathies.

Gene therapy has emerged as a promising curative treatment for β-hemoglobinopathies, the most common genetic disorders worldwide. However, current approved approaches still have some limitations in terms of safety and efficacy. Here, we used highly processive adenine base editor (ABE) variants to precisely correct some of the most prevalent and severe β-thalassemia-causing mutations in the β-globin-encoding HBB gene, including CD39 and IVS2-1, using NRCH-ABE8e and SpRY-ABE8e, respectively. More than 90% of editing of hematopoietic stem and progenitor cells (HSPCs) led to improved β-globin expression in their erythroid progeny and persistent correction of both β-thalassemia and sickle cell-β-thalassemia phenotypes. The safety of this strategy was confirmed in HSPCs in vitro and in vivo through the absence of gene dysregulation and any meaningful impact on the DNA mutational burden, RNA deamination, β-globin gene locus integrity, and the clonality of the HSPC graft, as assessed by RNA sequencing, whole-exome sequencing, long-read sequencing, and human HSPC transplantation in immunodeficient mice. Overall, these preclinical studies suggest that base editing-mediated gene correction may be a safe and effective strategy for treating β-hemoglobinopathies.

DOI: https://doi.org/10.1126/scitranslmed.adt8617

Blood. 2025 Nov 24. pii: blood.2025029969. [Epub ahead of print]

-IFN-γ increases δ-globin gene expression through activation of the JAK/STAT pathway in erythroid cells.

Jianqiong Zhu, Kyung Chin, Jizhong Zou, Wulin Aerbajinai, Wan-Chi Lin, Hongzhen Li, Griffin P Rodgers.

Sickle cell disease (SCD) and β-thalassemia, caused by mutations or deletions in the β-globin gene, are among the most prevalent genetic disorders worldwide, significantly impacting global health and mortality. Recently, reactivation of δ-globin gene expression has been proposed as a potential therapeutic strategy for these conditions. In this study, we found that IFN-γ and IFN-β significantly enhance δ-globin expression and activate the JAK/STAT signaling pathway in erythroid cells, with IFN-γ exerting a stronger effect than IFN-β. In erythroid cells derived from CD34⁺ progenitors, IFN-γ not only increased δ-globin expression but also promoted differentiation, as confirmed by quantitative PCR, Western blotting, high-performance liquid chromatography, and flow cytometry. Inhibition of the JAK/STAT pathway, either through a JAK1/2 inhibitor (AZD1840 or ruxolitinib) or via siRNAs targeting JAK1, JAK2, STAT1, and STAT3, significantly decreased both basal and IFN-γ-induced δ-globin expression in HBD-HiBiT knock-in HUDEP2 cells. Mutation or removal of the putative IRF-1/STAT2 binding site (-265 to -242) and the adjacent STAT binding site (-243 to -231) in the δ-globin promoter impaired IFN-γ-induced δ-promoter activity. ChIP assays confirmed enhanced binding of IRF-1 and STAT1 upon IFN-γ treatment. Our elucidation of the mechanism by which a specific molecule induces δ-globin expression suggests that IFN-γ may hold therapeutic potential for patients with SCD, and that screening for compounds that can induce δ-globin could offer a novel pharmaceutical strategy for treating β-hemoglobinopathies.

DOI: https://doi.org/10.1182/blood.2025029969

Biomed Rep. 2026 Jan;24(1): 8

Genotypic and hematological profiling of thalassemia in reproductive-age and pediatric populations.

Yanhong Liu, Wei Ye, Yan Zhang, Tailang Yin, Jingwei Wang.

Thalassemia is mainly prevalent in southern China, but consistent regional epidemiological data remain scarce in Hubei Province (central China). The present study characterized thalassemia genotypes and hematological parameters in 2,604 non-selectively screened individuals of reproductive-age (mean age, 31.39±5.72 years) and 407 pediatric subjects (mean age, 3.19±4.31 years) with clinical indications enrolled at Renmin Hospital of Wuhan University (Wuhan, Hubei), from January 2019 to September 2024. Peripheral blood and serum samples were analyzed for red blood cell count (RBC), hemoglobin (Hb), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), serum iron, total iron binding capacity, serum ferritin (SF), folate, transferrin saturation and vitamin B12 (VITB12) levels. Genetic testing was performed using gap-polymerase chain reaction (gap-PCR), reverse dot blot, Sanger sequencing and research-grade gap-PCR. The overall thalassemia carrier rates were 14.94% (reproductive-age group), 37.35% (pediatric group), and 17.97% (combined). Common α-thalassemia genotypes included--SEA/αα and -α3.7/αα, and dominant β-thalassemia mutations were β654, β41-42 and β17, aligning with neighboring provinces, differing from southern high-prevalence regions. Most phenotypes exhibited reduced RBC, Hb, MCV, MCH (all P<0.01) and elevated SF, VITB12. The high pediatric carrier rate may stem from selection bias due to clinical enrollment criteria. Notably, Hb and MCH were effective screening markers. In conclusion, Hubei has a substantial thalassemia burden (especially in children), and enhanced prenatal screening/counseling is urgently needed.

Keywords: genotype characteristics; hematological indicators; pediatric population; reproductive-age population; thalassemia

DOI: https://doi.org/10.3892/br.2025.2081