bims-sicedi 2025-01-19 papers

Am J Hematol. 2025 Jan 16.

Residual Cerebrovascular Morbidity Despite Treatment in Pediatric Sickle Cell Disease Highlights Opportunities for Earlier, Intensified Monitoring and Treatment.

Giulia Reggiani, Beatrice Coppadoro, Maria Paola Boaro, Roberta Trapanese, Ilaria Baido, Alessandra Biffi, Federica Viaro, Alessio Pieroni, Matteo Minerva, Giovanna Barcelos, Renzo Manara, Claudia Baracchini, Raffaella Colombatti.

DOI: https://doi.org/10.1002/ajh.27596

BMJ. 2025 Jan 10. 388 r37

Acute painful crisis in sickle cell disease: transfusion is not a benign treatment.

Sonia N Wolf.

DOI: https://doi.org/10.1136/bmj.r37

Mol Biotechnol. 2025 Jan 10.

CRISPR/Cas9 System as a Promising Therapy in Thalassemia and Sickle Cell Disease: A Systematic Review of Clinical Trials.

Rehab Ahmed, Wafa N Alghamdi, Fetun R Alharbi, Huda D Alatawi, Kawthar M Alenezi, Turki F Alanazi, Nehal M Elsherbiny.

Clustered, regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein (Cas) system is a new gene editing tool that represents a revolution in gene therapy. This study aimed to review the clinical trials conducted to evaluate the efficacy and safety of the CRISPR/Cas9 system in treating thalassemia and sickle cell disease (SCD). We searched relevant literature using "CRISPR Cas", "thalassemia", "sickle cell" and "clinical trial" as subject terms in PubMed, Cochrane, Web of Science, and Google Scholar up to December 3rd, 2023. Following the PIO format (Patients, Intervention, Outcome), PRISMA guidelines were followed in the study selection, data extraction, and quality assessment processes. Out of 110 publications, 6 studies met our eligibility criteria with a total of 115 patients involved. CRISPR/Cas9 system was used to disrupt BCL11A gene enhancer in 4 studies and to disrupt γ-globin gene promoters in 2 studies. Patients demonstrated significant activation of fetal hemoglobin, elevated total hemoglobin, transfusion independence in thalassemia, and repression of vaso-occlusive episodes in SCD. Using CRISPR/Cas9 system to directly disrupt genes provides a safe and potential one-time functional cure for thalassemia and SCD, suggesting CRISPR/Cas9 as a potential therapeutic tool for the treatment of inherited hematological disorders.

Keywords: CRISPR/Cas9 system; Fetal hemoglobin; Sickle cell disease; Thalassemia; Therapy

DOI: https://doi.org/10.1007/s12033-025-01368-x

Tissue Cell. 2025 Jan 04. pii: S0040-8166(24)00418-X. [Epub ahead of print]93 102717

Disrupted homeostasis in sickle cells: Expanding the comprehension of metabolism adaptation and related therapeutic strategies.

Victoria Simões Bernardo, Flaviene Felix Torres, Ana Clara Albertin Zucão, Nayara Alves Chaves, Ilana Luize Rocha Santana, Danilo Grünig Humberto da Silva.

Sickle cell disease (SCD) is a hereditary hemolytic anemia associated with the alteration of the membrane composition of the sickle erythrocytes, the loss of glycolysis, dysregulation of the pyruvate phosphatase pathway, and changes in nucleotide metabolism of the sickle red blood cell (RBC). This review provides a comprehensive overview of the impact of the presence of Hb S, which leads to the disruption of the normal RBC metabolism. The intricate interplay between the redox and energetic balance in erythrocytic cells, where the glycolysis, pentose phosphate pathway, and methemoglobin reductase pathways are all altered in sickle RBC, is a key focus. Moreover, this review summarizes the current knowledge about the disease-modifying agents and their action mechanisms based on the sickle RBC alterations previously mentioned (i.e., their association with beneficial effects on the sickle cells' membrane, to their RBCs' energy metabolism, and to their oxidative status). Therefore, providing a comprehensive understanding of how sickle cells cope with the disruption of metabolic homeostasis and the most promising therapeutic agents able to ameliorate the various consequences of abnormal sickle RBC alterations.

Keywords: Antioxidant capacity; Erythrocyte metabolism; Hemoglobin S; Sickle cell disease

DOI: https://doi.org/10.1016/j.tice.2024.102717

Genet Med Open. 2024 ;2 101875

Casgevy (exagamglogene autotemcel) and Lyfgenia (lovotibeglogene autotemcel) for individuals 12 years and older with sickle cell disease (SCD) and recurrent vaso-occlusive crises (VOC): A therapeutics bulletin of the American College of Medical Genetics and Genomics (ACMG).

ACMG Therapeutics Committee8∗documents@acmg.net

Keywords: Casgevy; Gene therapy; Lyfgenia; Sickle cell disease; Vaso-occlusive crises

DOI: https://doi.org/10.1016/j.gimo.2024.101875

Blood Adv. 2025 Jan 16. pii: bloodadvances.2024014327. [Epub ahead of print]

Stroke Prevention in Hispanic Children with Sickle Cell Anemia: the SACRED trial.

Sickle cell anemia (SCA) is recognized globally, but little is known about affected Hispanic populations. In partnership with Dominican Republic, a Hispanic Caribbean Island with a large SCA population, a TCD screening program provided hydroxyurea to children with conditional velocities. Building local capacity, ten Dominican medical graduates were certified in TCD examinations and trained in hydroxyurea management. Stroke Avoidance for Children in REpública Dominicana trial (SACRED, NCT02769845) enrolled 283 children with average age 8.7±3.4 years and 130 (46%) females. At initial screening, treatment-naïve children with conditional velocities (170-199 cm/sec) were younger (6.6±2.7 versus 8.9±3.4 years, p=.0002) and more anemic (hemoglobin 7.4±0.8 versus 8.0±1.2 g/dL, p=.0046) than children with normal screening velocities (<170 cm/sec). Among 57 treatment-naïve children receiving six months of fixed-dose hydroxyurea at 20 mg/kg/day, average TCD velocities decreased 20 cm/sec and 61% became normal. Compared to fixed-dose hydroxyurea, dose escalation to maximum tolerated dose (MTD) led to fewer sickle-related events with incidence rate ratio 0.59, 95% Confidence Intervals 0.36-0.98, p=0.0420. At MTD, TCD benefits were sustained over 5 years, with 81% reverting to normal and average TCD velocity decrease of 27 cm/sec. Brain MRI documented substantial baseline parenchymal disease; during hydroxyurea treatment 10% developed new vasculopathy, plus one stroke and one death. SACRED documents a high burden of cerebrovascular disease among Hispanic children with SCA, but also demonstrates the feasibility of partnership to establish TCD screening programs, the utility of hydroxyurea to reduce TCD velocities and reduce stroke risk, and the sustained benefits of hydroxyurea dose escalation.

DOI: https://doi.org/10.1182/bloodadvances.2024014327

Blood. 2025 Jan 16. 145(3): 255-256

B-1 B cells lose self-control in SCD.

David R Gibb, Sean R Stowell.

DOI: https://doi.org/10.1182/blood.2024026549