bims-sicedi 2025-08-17 papers

Ann Hematol. 2025 Aug 14.

Genetic modifiers of frequent vaso-occlusive hospitalizations among individuals with sickle cell disease (SCD).

Mina Cintho Ozahata, Isabel Gomes, Beatriz A Oliveira, Miriam Park, Daniela O W Rodrigues, Anna Bárbara Carneiro-Proietti, Cláudia Máximo, Allison Ashley-Koch, Marilyn Telen, Shannon Kelly, Brian Custer, Ester Cerdeira Sabino, Carla Luana Dinardo.

Sickle cell disease (SCD) is characterized by painful vaso-occlusive crises (VOC), which occur due to the adhesion of sickled erythrocytes and leukocytes to the endothelium, leading to vascular obstruction and tissue ischemia. Recurrent VOC increases SCD morbidity, reduces quality of life, and results in frequent hospitalizations. While factors like HbF levels and alpha-thalassemia co-occurrence are known to influence the risk of VOC, the genetic basis of this phenotype remains underexplored. To address this, we conducted a Genome-Wide Association Study (GWAS) to identify genetic predictors of frequent VOC in SCD patients. The study focused on patients with the SS genotype, analyzing those who experienced three or more pain crisis hospitalizations annually. To account for population substructure, the top 10 principal components were included. The GWAS was performed using ENCORE and the Saige Logistic Mixed Model, adjusted for hydroxyurea treatment as a covariate, with a genome-wide significance threshold of 5 × 10-8. The study included 125 cases and 1670 controls, revealing 9 significant SNPs. 8 were associated with the CTNNA2 gene (p-value = 7.77 × 10-9), and 1 with METTL4 (p-value = 3.39 × 10-8). These findings highlight the role of CTNNA2 and METTL4 in VOC hospitalizations, providing insights into the genetic underpinnings of SCD pain.

Keywords: Gwas; Pain; Sickle cell; Vaso-occlusive crises

DOI: https://doi.org/10.1007/s00277-025-06547-z

EJHaem. 2025 Aug;6(4): e70111

Trends, Predictors, and Outcomes of Critically Ill Patients With Sickle Cell Disease in the United States.

Tochukwu Nzeako, Olayemi Adeniran, Saranjeet Kaur, Shreya Singh, Jen Wang, Ammar Alzoubi.

Introduction: Despite recent advances in sickle cell disease (SCD) research and management, there remains very limited information available on critically ill SCD patients requiring intensive care units (ICUs).
Methods: The National Inpatient Sample was queried using the International Classification of Diseases codes to identify critically ill patients with SCD requiring ICU admission. These patients were further stratified into those with and without adverse clinical events (ACEs). The study outcomes were the incidence of acute chest syndrome, cardiac arrest, hemodialysis, sepsis, shock, and transfusion.
Results: Of 5941 patients admitted to the ICU, 2826 (47.6%) had ACE. Patients with ACE were likely to be older, male, white, rural, and have higher comorbidities. The prevalence of ICU admission increased by 126% (p < 0.01). The predictors of ACE included male sex, older age, coronary artery disease, heart failure, renal failure, and two or more comorbidities. Patients with ACE were more likely to have cardiac arrest, hemodialysis, sepsis, and shock (all p < 0.01).
Conclusion: There has been an increase in the prevalence of critically ill SCD patients requiring ICU care, with subsequent morbidity and mortality. Further research is needed to understand the underlying factors that drive these observed trends and increase mortality rates.
Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.

Keywords: adverse clinical events; critically ill; intensive care unit; sickle cell disease

DOI: https://doi.org/10.1002/jha2.70111

Hemoglobin. 2025 Aug 12. 1-6

Sickling Disorder Caused by Co-Inheritance of Hemoglobin Maputo and Hemoglobin S: Case Report and Review of the Literature.

Sakina Loonat, Nitien Naran, Narisha Ramparsad, Nadia Beringer, Mishalan Moodly, Arshad Ismail, Michelle Bronze, Gail Faller, Nazeer Alli.

We report a family study wherein the index patient, a 6-year-old Mozambican female, was diagnosed with compound heterozygous HbS and Hb Maputo. She presented with acute pain, swelling and tenderness in the right fronto-temporal region of the skull, which raised suspicion of sickle cell disease (SCD). Prior to this presentation, a two-year history of vague clinical symptoms (viz., periodic fever, joint pain and abdominal pain) was obtained. Both parents were clinically asymptomatic. Hemoglobin separation studies were performed using hemoglobin electrophoresis and high performance liquid chromatography. Next generation sequencing technology was employed for gene sequencing analysis of globin genes. Both parents were also fully investigated. Hemoglobin separation studies on the index patient detected two hemoglobin variants that were identified on gene sequencing analysis as HbS and Hb Maputo. The mother and father were demonstrated to have heterozygous HbS and Hb Maputo, respectively. The α globin genes in all the family members had a normal wild type configuration. Conclusion: Hb Maputo in the heterozygous state is an uncommon β chain variant that is clinically silent whereas co-inheritance of Hb Maputo and HbS causes a sickling disorder with vaso occlusive disease.

Keywords: Sickle cell disease; compound heterozygosity; hemoglobin Maputo; rare hemoglobin variant

DOI: https://doi.org/10.1080/03630269.2025.2537094

Nat Biomed Eng. 2025 Aug 12.

In vivo genome editing of human haematopoietic stem cells for treatment of blood disorders using mRNA delivery.

Saijuan Xu, Dan Liang, Qiudao Wang, Yan Cheng, Da Xie, Yang Gui, Haokun Zhang, Changrui Feng, Feiyan Zhao, Wendan Ren, Gongrui Sun, Yang Yang, Lin Li, Yongrong Lai, Bin Fu, Yuming Lu, Zi Jun Wang, Yuxuan Wu.

Ex vivo autologous haematopoietic stem cell (HSC) gene therapy provides a promising treatment option for haematological disorders. However, current methods involve complex processes and chemotherapeutic conditioning, leading to limited accessibility for treatment and major side effects. Here we develop antibody-free targeted lipid nanoparticles (LNPs) for mRNA delivery to HSCs in vivo, enabling efficient base editing of the γ-globin gene (HBG1/2) promoter target in human HSCs to reactivate fetal haemoglobin in derived erythroid cells. Delivery of ABE8e/sgRNA mRNA with optimized LNPs achieves efficient in vivo base editing of HBG1/2 in transfusion-dependent β-thalassaemia (TDT) patient-derived HSCs engrafted in immunodeficient NCG-X mice, showing restored globin chain balance in erythroid cells. Our research indicates that using LNPs for genome editor delivery achieves efficient editing of endogenous genes of human HSCs. This non-viral delivery system eliminates the need for collecting or mobilizing HSCs, providing a potent and one-time treatment potential for blood disorders such as sickle cell disease and TDT.

DOI: https://doi.org/10.1038/s41551-025-01480-y