bims-sicedi Biomed News
on Sickle cell disease
Issue of 2025–05–18
eight papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo
  1. Innovations in Drug Discovery for Sickle Cell Disease Targeting Oxidative Stress and NRF2 Activation-A Short Review.
  2. Rpl13a snoRNAs U34 and U35a: New Targets for Sickle Cell Disease Complications.
  3. Comparative Proteomic Analysis Reveals Altered Ciliary Proteins in Sickle Cell Disease.
  4. Alterations in the humoral immunophenotype in sickle cell disease.
  5. Prevalence and Significance of Pancreatic Iron in Transfusion-Dependent Sickle Cell Disease.
  6. HCAR2 is a novel receptor for heme.
  7. Genetic Modifiers Associated with Vaso-Occlusive Crises and Acute Pain Phenomena in Sickle Cell Disease: A Scoping Review.
  8. Discovery of potent substrate-type lysine methyltransferase G9a inhibitors for the treatment of sickle cell disease.
  1. Int J Mol Sci. 2025 Apr 28. pii: 4192. [Epub ahead of print]26(9):
    Innovations in Drug Discovery for Sickle Cell Disease Targeting Oxidative Stress and NRF2 Activation-A Short Review.
    Athena Starlard-Davenport, Chithra D Palani, Xingguo Zhu, Betty S Pace.
      Sickle cell disease (SCD) is a monogenic blood disorder characterized by abnormal hemoglobin S production, which polymerizes under hypoxia conditions to produce chronic red blood cell hemolysis, widespread organ damage, and vasculopathy. As a result of vaso-occlusion and ischemia-reperfusion injury, individuals with SCD have recurrent pain episodes, infection, pulmonary disease, and fall victim to early death. Oxidative stress due to chronic hemolysis and the release of hemoglobin and free heme is a key driver of the clinical manifestations of SCD. The net result is the generation of reactive oxygen species that consume nitric oxide and overwhelm the antioxidant system due to a reduction in enzymes such as superoxide dismutase and glutathione peroxidase. The primary mechanism for handling cellular oxidative stress is the activation of antioxidant proteins by the transcription factor NRF2, a promising target for treatment development, given the significant role of oxidative stress in the clinical severity of SCD. In this review, we discuss the role of oxidative stress in health and the clinical complications of SCD, and the potential of NRF2 as a treatment target, offering hope for developing effective therapies for SCD. This task requires our collective dedication and focus.
    Keywords:  NRF2; fetal hemoglobin; glutathione; heme; hemoglobin S; hemolysis; oxidative stress; reactive oxygen species; sickle cell disease
    DOI:  https://doi.org/10.3390/ijms26094192
  2. Circ Res. 2025 May 15.
    Rpl13a snoRNAs U34 and U35a: New Targets for Sickle Cell Disease Complications.
    Waseem Chauhan, Sudharshan Setra Janardhana Shetty, Shirin Ferdowsi, Sweta Kafle, Rahima Zennadi.
       BACKGROUND: In sickle cell disease (SCD), erythrocyte reactive oxygen species (ROS) production and oxidative stress play a critical role in vaso-occlusion, a hallmark of SCD. Small noncoding nucleolar RNAs (snoRNAs) of the Rpl13a locus have been described as regulators of ROS levels. However, whether Rpl13a snoRNAs are present in sickle red blood cells (RBCs) and regulate ROS levels and whether they contribute to SCD pathophysiology remain unknown.
    METHODS: To determine whether sickle RBC ROS levels are associated with Rpl13a snoRNA levels and identify the mechanism by which they regulate ROS and snoRNAs' effects on SCD hemodynamics, we used human RBCs, Rpl13a snoRNA knockout sickle mice, K562 U32a, U33, U34, U35a, and the control U25 knockout mutants generated by CRISPR-Cas9-targeted genome editing, and genetic targeting with antisense oligonucleotides.
    RESULTS: Excessive ROS production in sickle RBCs of patients with SCD is associated with high Rpl13a snoRNAs U32a, U33, U34, and U35a levels. U32a, U34, and U35a regulate ROS and hydrogen peroxide levels in sickle erythroid populations by modulating peroxidase activity. This was due to U32a- and U34-guided 2'-O-methylation on Prdx2 (peroxiredoxin 2) messenger RNA, a modification conveyed by fibrillarin during erythropoiesis, subsequently reducing Prdx2 expression and activity. The snoRNA U35a impaired Prdx2 expression/activity but independently of Prdx2 messenger RNA 2'-O-methylation. Excess sickle RBC ROS increased in turn Rpl13a snoRNAs levels. In vivo targeting combinations of U34+U35a and U32a+U34+U35a in sickle mice with antisense oligonucleotide blunted RBC ROS generation, improved erythropoiesis and anemia, alleviated leukocytosis and endothelial damage, diminished cell adhesion in inflamed vessels and vaso-occlusion, restored blood flow, and reduced animal mortality.
    CONCLUSIONS: Rpl13a snoRNAs U34 and U35a specifically increase ROS levels, which, in turn, regulate snoRNA expression, in sickle erythroid cells, modulating Prdx2 expression/activity, subsequently impairing hemodynamics. Targeted U34+U35a with antisense oligonucleotide may represent a novel and safe therapy to ameliorate erythropoiesis and downstream events in SCD.
    Keywords:  RNA, small nucleolar; anemia, sickle cell; antioxidants; endothelium, vascular; reactive oxygen species
    DOI:  https://doi.org/10.1161/CIRCRESAHA.124.325093
  3. J Proteome Res. 2025 May 15.
    Comparative Proteomic Analysis Reveals Altered Ciliary Proteins in Sickle Cell Disease.
    Ashraf M Mohieldin, Madison Spencer, Carter Bernal, Wala B Fadol, Ankan Gupta, Karthikeyan Thirugnanam, Claire Delahunty, Francisco Nunez, Amy Y Pan, Amanda M Brandow, Sean P Palecek, Kevin R Rarick, Ramani Ramchandran, Rahima Zennadi, John Yates, Surya M Nauli.
      Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by sickle-shaped red blood cells (RBCs). Primary cilia are mechanosensory organelles and are projected in the lumen of blood vessels to detect blood flow. We previously reported that interaction between microvasculature endothelial cells and sickled RBCs resulted in altered blood flow that can elevate reactive oxygen species, leading to increased deciliation in SCD patients. However, the impact of deciliation mediated by sickled RBCs in the context of the ciliary protein profiles remains unclear. Here, we investigated cell-cilia stability under different physiological shear-stress magnitudes and examined cilia protein profiles in SCD, utilizing mouse models and human participants. Our results demonstrate that subjecting endothelial cilia to sickled RBCs at 5.0 dyn/cm2 led to significant deciliation events. The proteomic and bioinformatic analyses showed different ciliary protein profiles, distinct signaling pathways, and unique post-translational modification processes in the SCD mouse model. Consistent with the SCD mouse model results, our translational studies validated the enrichment of specific proteins, including Transferrin Receptor-1 (TfR1), Glyceraldehyde-3-Phosphate-Dehydrogenase (GAPDH), and ADP Ribosylation Factor Like GTPase-13B (ARL13B) in SCD patients. These findings underscore the clinical relevance of cilia in SCD and suggest that ciliary proteins are potential biomarkers for assessing vascular damage.
    Keywords:  diagnostic biomarker; extracellular vesicles; primary cilia; proteomics; red blood cells; sickle cell disease; sickle cell trait; vascular damage
    DOI:  https://doi.org/10.1021/acs.jproteome.5c00168
  4. Br J Haematol. 2025 May 14.
    Alterations in the humoral immunophenotype in sickle cell disease.
    E Vistica Sampino, D M Bonal, A Chorzalska, J Morgan, L Nguyen, C Yu, A Rodriguez, R De Vito, S Pels, P G Sprinz, P McGann, R R Lulla, P M Dubielecka.
      The pathophysiology of sickle cell disease (SCD) is linked to haemolysis and systemic inflammation. To determine the range of systemic alterations, we assessed the frequency of 12 immune populations and the levels of related cytokines in the peripheral blood of paediatric (n = 13) and adult (n = 12) patients with SCD prescribed hydroxyurea, as compared to paediatric (n = 5) and adult (n = 10) race-matched controls. Transcriptome analysis of the peripheral blood of paediatric SCD patients and controls was also performed. Flow cytometry showed a 3.5-fold increase (p = 0.005) in CD19+ B cells in paediatric SCD and a 52% decrease in central memory B cells (p = 0.002) in adult SCD. Paediatric transcriptomic data revealed significant upregulation of pro-B cell transcripts (27 genes, top 3: E2F2, RAD51, ASPM) and plasma cell transcripts (37 genes, top 3: IGF1, TNFRSF17, DERL3). Cytokine analyses showed significant increases in IL-2 (p = 0.013), IL-4 (p = 0.026), TNFβ (p = 0.039), IL-13 (p = 0.034) and BAFF (p = 0.041) in paediatric SCD, and an increase in CD40L and BAFF in adult SCD. In summary, our data showed alterations in the humoral immophenotype in paediatric SCD, specifically an increase in CD19+ B cells, suggesting there may be significant alterations of homeostasis in the humoral immune system in children with SCD treated with hydroxyurea.
    Keywords:  B cell; humoral immune system; hydroxyurea; inflammation; sickle cell disease
    DOI:  https://doi.org/10.1111/bjh.20089
  5. Pediatr Blood Cancer. 2025 May 12. e31780
    Prevalence and Significance of Pancreatic Iron in Transfusion-Dependent Sickle Cell Disease.
    Akhila Vadivelan, Eamon Doyle, Susan Carson, Christopher Denton, Saranya Veluswamy, Thomas Hofstra, Thomas Coates, John C Wood.
       BACKGROUND: Chronically transfused patients with sickle cell disease (SCD) and beta thalassemia major (TM) develop iron overload.
    OBJECTIVE: Determine the impact of iron overload on glucose regulation in SCD.
    METHODS: Prospective study of 28 patients with SCD and 38 patients with TM who underwent liver and pancreas R2* measurements and oral glucose tolerance tests.
    RESULTS: Impaired fasting glucose (2 vs. 9, p = 0.27) and impaired glucose tolerance (1 vs. 11, p = 0.019) were less common in patients with SCD compared with patients with TM. No SCD patient had diabetes.
    CONCLUSION: Iron-mediated glucose dysregulation is present but less common in SCD patients.
    Keywords:  pancreatic siderosis; sickle cell disease; transfusion dependent
    DOI:  https://doi.org/10.1002/pbc.31780
  6. Blood Adv. 2025 May 09. pii: bloodadvances.2025016197. [Epub ahead of print]
    HCAR2 is a novel receptor for heme.
    Anne Grunenwald, Julie Peliconi, Alessandra Zarantonello, Jordan D Dimitrov, Lubka T Roumenina, Nicolas S Merle.
      Extracellular heme, released during intravascular hemolysis in sickle cell disease (SCD) and hemolytic anemia acts as a pro-inflammatory danger signal, requiring robust defense mechanisms. Previous studies identified GPCR signaling triggered by heme, but the specific receptor remained unknown. Transcriptomic analysis of bulk RNAseq of liver tissues from SCD and hemolytic mice (injection of phenylhydrazine) revealed GPCR signaling as a commonly enriched pathway. Unbiased screening of 241 GPCRs identified Hydroxycarboxylic Acid Receptor 2 (HCAR2/GPR109A), an anti-inflammatory receptor for niacin, as a novel heme sensor. Heme binding to human HCAR2 was validated using a functional reporter cell assay and direct interaction analyses via surface plasmon resonance and absorbance spectroscopy. In vivo, HCAR2 was upregulated in the liver of SCD and hemolytic mice, paralleling the expression of the heme-degrading enzyme heme oxygenase-1 (HO-1). HO-1 inhibition or heme injection further increased HCAR2 expression, indicating that heme acts as both a ligand and an inducer of HCAR2. These findings identify HCAR2 as a novel heme receptor and reveal a heme-HCAR2-HO-1 negative feedback loop, involved in tissue protection in hemolytic diseases.
    DOI:  https://doi.org/10.1182/bloodadvances.2025016197
  7. Int J Mol Sci. 2025 May 07. pii: 4456. [Epub ahead of print]26(9):
    Genetic Modifiers Associated with Vaso-Occlusive Crises and Acute Pain Phenomena in Sickle Cell Disease: A Scoping Review.
    International Hemoglobinopathy Research Network (INHERENT)
      Sickle cell disease (SCD) is a group of recessive diseases caused by the βS sickling mutation of HBB in homozygosity or in compound heterozygosity with other pathogenic HBB mutations. Patients with severe SCD typically experience painful vaso-occlusive crises and other pain-related phenomena, including acute chest syndrome, priapism, dactylitis, avascular necrosis, and splenic sequestration and infarction. High variability of pain-related phenomena per SCD genotype indicates genetic disease modifiers (GDMs) as pathology determinants and, thus, as critical to prognosis, treatment choice, and therapy development. Articles likely holding genetic information for SCD pain phenomena were identified in PubMed and SCOPUS for article quality assessment and extraction of corresponding GDMs and observations indicative of development areas in our understanding of SCD GDMs. This process led to the initial selection of 183 articles matching the search terms, which, after two-step selection, resulted in the inclusion of 100 articles for content analysis and of significant findings for GDMs from 37 articles. Published data point to gender effects and to 51 GDM SNVs, deletions, and regions, including globin genes and significant overrepresentation of gene ontology pathways related, e.g., to oxidative stress, hypoxia, and regulation of blood pressure. Analyzed articles further pointed to additional candidate GDMs affecting SCD VOC and pain phenomena and to potential confounding factors for GWAS analyses. We found that despite the critical importance of VOC and pain phenomena for SCD pathology, corresponding clinically relevant genetic insights are held back by a shortage of large-scale, systematic multi-ethnic efforts, as undertaken by the INHERENT Network.
    Keywords:  GWAS; acute chest syndrome; avascular necrosis; dactylitis; genetic disease modifier; hemoglobinopathy; priapism; sickle cell disease; splenic sequestration; vaso-occlusive crises
    DOI:  https://doi.org/10.3390/ijms26094456
  8. Eur J Med Chem. 2025 May 11. pii: S0223-5234(25)00486-6. [Epub ahead of print]293 117721
    Discovery of potent substrate-type lysine methyltransferase G9a inhibitors for the treatment of sickle cell disease.
    Yosuke Nishigaya, Shohei Takase, Tatsunobu Sumiya, Ko Kikuzato, Takashi Hiroyama, Yuki Maemoto, Komei Aoki, Tomohiro Sato, Hideaki Niwa, Shin Sato, Kentaro Ihara, Akiko Nakata, Seiji Matsuoka, Noriaki Hashimoto, Ryosuke Namie, Teruki Honma, Takashi Umehara, Mikako Shirouzu, Hiroo Koyama, Yukio Nakamura, Minoru Yoshida, Akihiro Ito, Fumiyuki Shirai.
      Structurally novel inhibitors of the lysine methyltransferase G9a have attracted considerable interest as potential drug candidates for cancer and genetic diseases. Here, a detailed account of potency optimization from early leads 8 and 9 to compound 16g is presented. Our search for an alternative scaffold for the 4-oxo-4,5,6,7-tetrahydro-1H-indole moiety of compounds 8 and 9 via parallel synthesis led to the identification of the 4-pyridin-4-ylamino phenyl substructure in compound 16g. This substructure was found to bind to the enzyme in a horizontally flipped manner compared with compound 8 in X-ray crystallographic analysis. Compound 16g is a highly potent G9a inhibitor (IC50 = 0.0020 μM) and structurally distinct from other G9a inhibitors reported in the literature. Importantly, compound 16g exhibited dose-dependent induction of γ-globin mRNA in HUDEP-2, leading to elevated γ-globin protein levels and F cell numbers in CD34+ bone marrow (BM)‒derived hematopoietic cells. Kinetic studies using surface plasmon resonance (SPR) analysis suggested that compound 16g interacts with G9a via a unique binding mode, as indicated by the markedly higher dissociation constant (KD) compared to those of compounds 8 and 9. Interestingly, X-ray crystallographic studies revealed that the binding motif of compound 16g was quite different from our previous series, including RK-701, and somewhat resembles that of endogenous substrates. Insights obtained in this lead optimization exercise on the association/dissociation constants as well as the binding motifs are expected to help in designing future G9a inhibitors for the treatment of sickle cell disease.
    Keywords:  Drug discovery; Histone methylation; Lysine methyltransferase G9a; Sickle cell disease; Substrate-type inhibitors; γ-globin mRNA
    DOI:  https://doi.org/10.1016/j.ejmech.2025.117721
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