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PubMed2026

Exa-cel in Children with Transfusion-Dependent β-Thalassemia or Sickle Cell Disease.

BACKGROUND: Exagamglogene autotemcel (exa-cel) is a cell therapy in which autologous CD34+ hematopoietic cells are engineered through ex vivo clustered regularly interspaced short palindromic repeats-Cas9 editing of the erythroid-specific enhancer region of BCL11A to express fetal hemoglobin. In phase 3 studies involving participants 12 to 35 years of age with sickle cell disease or transfusion-dependent β-thalassemia, exa-cel eliminated vaso-occlusive crises and the need for red-cell transfusions. METHODS: In two ongoing, phase 3, open-label, single-group studies, we evaluated exa-cel in children 5 to 11 years of age with transfusion-dependent β-thalassemia or sickle cell disease. Before exa-cel infusion, participants underwent myeloablative conditioning with pharmacokinetically dose-adjusted busulfan. The primary end points were transfusion independence for at least 12 consecutive months in children with transfusion-dependent β-thalassemia and freedom from severe vaso-occlusive crises for at least 12 consecutive months in children with sickle cell disease. RESULTS: A total of 15 children with transfusion-dependent β-thalassemia and 11 with sickle cell disease received exa-cel; median follow-up was 16.0 months (range, 2.2 to 32.1) and 16.9 months (range, 7.6 to 33.1), respectively. Of 8 children with transfusion-dependent β-thalassemia who were followed to at least 16 months, 8 were transfusion independent; the status of the remaining 7 was not yet evaluable. Of 8 children with sickle cell disease who were followed to at least 16 months, 8 were free of vaso-occlusive crises; the status of the remaining 3 was not yet evaluable. All the children had at least one grade 3 or 4 adverse event; 2 children with transfusion-dependent β-thalassemia had severe veno-occlusive liver disease that was assessed as being related to busulfan conditioning, 1 of whom died. CONCLUSIONS: Exa-cel therapy resulted in transfusion independence or freedom from severe vaso-occlusive crises in participants with transfusion-dependent β-thalassemia or sickle cell disease, respectively, who were followed for at least 16 months. All the participants had grade 3 or 4 adverse events. (Funded by Vertex Pharmaceuticals and CRISPR Therapeutics; CLIMB THAL-141 ClinicalTrials.gov number, NCT05356195; CLIMB SCD-151 ClinicalTrials.gov number, NCT05329649.).

Child↗
PubMed2026

Is There a Difference in Occurrence of Complications Between Adults With Hemoglobin SS and Hemoglobin SC Disease: An Extended Systematic Review.

Sickle cell disease (SCD) is characterized by both acute and chronic complications. The clinical manifestation of these complications differs between genotypes. Given the large amount of research already published, this systematic review aims to offer a complete overview of types of sickle cell complications between adults in the most common genotypes Hemoglobin SS (HbSS) and Hemoglobin SC (HbSC), putting options for further research into perspective. An extensive literature search was performed to study all available evidence on these complications. This review was performed according to the "Preferred Reporting Items for Systematic Reviews and Meta-Analyses" (PRISMA) statement guidelines, and was performed on January 2, 2024. A total of 710 references were identified. After careful screening, 521 records were excluded based on title and abstract and other exclusion criteria. In total, 158 articles were excluded after full-text assessment. Our analysis of 31 studies highlights key differences in complications between HbSS and HbSC genotypes in sickle cell disease (SCD). Vaso-occlusive crises (VOCs) remain the most common acute complication in both genotypes. HbSS patients experience more frequent VOCs, while HbSC patients generally have a milder clinical course when it comes to acute complications. Chronic complications, particularly in the ocular and pulmonary systems, are more prevalent in HbSC patients. However, as acute complications are more common in HbSS and chronic complications more common in HbSC, both genotypes face progressive organ damage due to recurrent ischemic injury and inflammation.

Humans↗
PubMed2026

Plasma Proteome Signatures in Sickle Cell Anemia and the Effect of Hydroxyurea Treatment.

Sickle Cell Anaemia (SCA) is a monogenic blood disorder caused by a mutation in the β-globin gene, yet it presents with marked clinical variability. Although hydroxyurea (HU) is an established therapy, its precise mechanism of action remains incompletely understood. Plasma proteins represent valuable biomarkers for elucidating disease mechanisms and treatment responses. In this study, plasma proteome profiling of 31 healthy controls and 76 SCA patients identified 43 differentially abundant proteins (DAPs) that form a highly interconnected interaction network. Proteins with increased abundance in SCA were largely associated with immune and inflammatory responses, whereas those with reduced levels were linked to coagulation and proteolytic pathways. HU therapy was associated with elevated levels of haptoglobin (HP) and hemopexin (HPX), key mediators of free hemoglobin scavenging. We also identified several previously unreported plasma proteins altered in SCA, broadening the landscape of potential biomarkers and HU-responsive targets. Many DAPs significantly correlated with clinical indices, such as transfusion frequency, vaso-occlusive crises, white blood cell counts, and platelet counts, offering insights into disease mechanisms and potential utility in disease management. Notably, overlap with β-thalassemia-associated signatures suggests shared pathophysiological pathways between these hemoglobinopathies. Collectively, these findings provide a strong foundation for translational validation in larger, independent cohorts.

Humans↗
PubMed2026

Systematic review of machine learning approaches for predicting sickle cell crisis and mortality risk at the climate-health nexus.

BACKGROUND: Sickle cell anemia (SCA) is a severe genetic blood disorder characterized by recurrent vaso-occlusive crises and increased mortality, with the greatest burden occurring in low- and middle-income countries. Climatic and environmental conditions, including temperature variability, humidity, rainfall, air pollution, and seasonal changes, have been associated with disease exacerbation. However, the extent to which these factors have been incorporated into predictive models remains unclear. This study systematically reviews the application of machine learning (ML) models for predicting SCA crises and mortality in relation to climate and environmental factors. METHODOLOGY: The PRISMA guidelines were used, and 34 peer-reviewed studies published between 2005 and 2026 were analyzed to identify the climate variables, ML approaches employed, and predictive performance. The reviewed studies applied a range of ML techniques, including artificial neural networks, random forests, support vector machines, decision trees, logistic regression, and deep learning models. Temperature, humidity, rainfall, wind speed, air quality indicators, and seasonal patterns were the most frequently examined environmental variables. RESULTS: The findings indicate that most existing models rely predominantly on clinical and demographic data, with limited integration of climate information and inadequate representation of high-burden regions, especially Sub-Saharan Africa. Studies incorporating environmental variables reported improved predictive performance and highlighted the potential of climate-informed early warning systems for SCA management. CONCLUSION: The review recommends development of interdisciplinary, climate-aware ML frameworks, expansion of longitudinal environmental datasets, and increased research in underrepresented regions to support climate-resilient and patient-centered SCA care.

Humans↗
PubMed2026

Secretory Phospholipase A2 in Patients With Sickle Cell Disease Hospitalized for Vaso-Occlusive Pain Episodes.

BACKGROUND: Secretory phospholipase A2 (sPLA2) is an inflammatory mediator linked to acute chest syndrome (ACS) in sickle cell disease (SCD), a serious complication that can develop during an acute vaso-occlusive pain episode (VOE). Plasma sPLA2 levels have been proposed as a potential biomarker for predicting ACS onset. OBJECTIVE: To assess serial plasma sPLA2 levels in 105 pediatric patients hospitalized for SCD-VOE and determine the effects of arginine therapy compared to placebo. PROCEDURES: This is a pharmacokinetics/pharmacodynamics and randomized controlled trial of intravenous arginine therapy. Statistical methods included t-tests, chi-square, and correlation analyses. RESULTS: Mean age was 12.7 &#xb1; 3.7 years, 48% were male, 67% had Hb-SS, and 70% were prescribed hydroxyurea. Using a previously established SCD-specific cutoff of 48&#xa0;ng/mL, presenting sPLA2 levels were elevated in 33% of patients (mean sPLA2 level 85.7 &#xb1; 32.9&#xa0;ng/mL). SPLA2 elevation in the emergency department was more common in patients with ACS compared to those without ACS (64%&#xa0;vs. 30%; p = 0.02; negative predictive value of 94%). Peak sPLA2 levels were significantly higher in febrile (n = 34) versus afebrile patients (n = 71;101.0 &#xb1; 45.3 vs. 48.7 &#xb1; 35.4&#xa0;ng/mL; p < 0.0001). Among subjects with elevated baseline sPLA2, arginine therapy resulted in a significant reduction in sPLA2 levels by discharge compared to placebo (-27.8 &#xb1; 38.1&#xa0;ng/mL; p = 0.002; n = 23&#xa0;vs. -15.0 &#xb1; 41.2&#xa0;ng/mL; p = 0.23; n = 12). CONCLUSIONS: SPLA2 is an underutilized biomarker of ACS given accumulating evidence of its role. In particular, low levels may identify patients at low risk for ACS. Arginine therapy may modulate inflammation in patients with SCD during VOE and/or ACS. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT02447874; NCT02536170.

Humans↗
PubMed2026

Gene expression profiling identifies potential biomarkers for vaso-occlusive episodes in sickle cell disease.

Vaso-occlusive episodes (VOEs) or acute pain events, involving complex interactions between sickle erythrocytes and other blood cells, are a hallmark of sickle cell disease (SCD). In this study, we analyzed changes in peripheral blood transcriptomes between steady state and VOEs in individuals with SCD. We followed a cohort of 174 individuals with SCD with or without chronic pain and collected peripheral blood at clinic visits (steady state) and during hospitalizations (VOEs). We performed RNA-Seq profiling of CD45+ leukocytes and CD71+ erythroid cells. Pathways linked to complement activation, coagulation, and IL-6/JAK/STAT3 signaling were enriched during VOEs in the CD45+ cells. Contrastingly, the CD71+ cells showed an enrichment of pathways related to the cell cycle, such as mTORC1 signaling and the G2M checkpoint during VOEs. We then analyzed the expression changes of genes in patients with longitudinal data to determine potential biomarkers for VOEs. Expression of 4 genes - FAM20A, IL1B, MS4A4A, and SERPINB2 - was elevated during VOEs compared with steady state in the majority of patients. Furthermore, our results indicate that patients experiencing chronic pain exhibited 44% increased enrichment of significant pathways during VOEs when compared with patients without chronic pain.

Humans↗