bims-conane 2025-04-27 papers

Curr Res Transl Med. 2025 Apr 12. pii: S2452-3186(25)00022-4. [Epub ahead of print]73(3): 103513

Therapeutic promise of CRISPR-Cas9 gene editing in sickle cell disease and β-thalassemia: A current review.

Sickle cell disease (SCD and β-thalassemia (BT) affects millions of people worldwide. In addition, around 500,000 infants are born with SCD and 60,000 people are diagnosed with BT every year. Mutations in the hemoglobin subunit beta (HBB) gene are responsible for causing both BT and SCD. Indeed, the diversity of potential mutations in the HBB gene elucidates the diversity in clinical severity observed in individuals with BT and related morbidities. On the other hand, SCD takes place because of the alteration in a single amino acid at position 6 in the beta-globin chain, where a base substitution occurs from glutamic acid to valine, which eventually results in abnormal sickle hemoglobin. Conventional therapies for BT and SCD including pharmaceutical drugs and blood transfusion might temporarily improve the clinical severity of these diseases, however these therapies cannot cure the diseases. CRISPR-Cas9 (CC9) is revolutionizing genome engineering, offering promising therapeutic avenues for genetic diseases. Therefore, CC9-mediated gene therapy provides great hope in the treatment of both BT and SCD. CC9-mediated gene therapy has already demonstrated its effectiveness in correcting both SCD and BT-causing mutations. Moreover, CC9-mediated gene editing was found to be effective in reactivating the expression of hemoglobin F (HbF) and regulating LRF and BCL11A. A number of clinical trials with CC9 gene-edited therapies are being carried out to elucidate their potential in treating BT and SCD. Genetics and pathophysiological mechanisms of SCD and BT, the mechanism of CC9-mediated gene editing, and common delivery methods of the CC9 system have been discussed in this review. Moreover, an in-depth discussion on applications and the current status of CC9-mediated gene editing in SCD and BT along with current challenges and future perspectives have been provided.

Keywords: CRISPR-Cas9; Hemoglobin F; Mutations; Sickle cell disease; β-thalassemia

DOI: https://doi.org/10.1016/j.retram.2025.103513

Development. 2025 Apr 22. pii: dev.204485. [Epub ahead of print]

The Condensin II complex regulates the expression of essential gene expression programs during erythropoiesis.

Deanna Abid, Kristin Murphy, Zachary Murphy, Nabil Rahman, Michael Getman, Laurie Steiner.

Erythropoiesis is characterized by dramatic changes in gene expression in the context of a cell that is rapidly proliferating while simultaneously condensing its nucleus in anticipation of enucleation. The mechanisms that maintain high level expression of erythroid genes and promote nuclear condensation remain poorly understood. Condensin II is a ring-like complex that promotes mitotic chromatin condensation and has roles in regulating interphase chromatin architecture and gene expression. We interrogated the role of Condensin II in erythropoiesis using an erythroid-specific deletion of the Condensin II subunit, Ncaph2. Ncaph2 loss resulted in severe anemia by embryonic day (E) 12.5 with embryonic lethality. Ncaph2 mutant erythroid cells had dysregulated maturation and disrupted cell cycle progression, but surprisingly Ncaph2 was dispensable for nuclear condensation. Genomic studies revealed that Ncaph2 occupied the promoter of key erythroid and cell cycle genes that were downregulated following Ncaph2 loss. Together, our results demonstrate an essential role for Ncaph2 in the gene expression programs that regulate cell cycle progression and erythroid differentiation, and identify a role for the Condensin II complex in the regulation of a lineage-specific differentiation program.

Keywords: Cell cycle; Condensin II Complex; Epigenetic; Erythropoiesis; H4K20me1

DOI: https://doi.org/10.1242/dev.204485

Hematol Rep. 2025 Apr 15. pii: 20. [Epub ahead of print]17(2):

Hemolytic Anemia Due to Gamma-Glutamylcysteine Synthetase Deficiency: A Rare Novel Case in an Arab-Muslim Israeli Child.

Motti Haimi, Jamal Mahamid.

BACKGROUND: Gamma-glutamylcysteine synthetase catalyzes the first and rate-limiting step in the synthesis of glutathione. Gamma-glutamylcysteine synthetase deficiency is a very rare condition that has so far been detected so far in nine patients from seven families worldwide. The inheritance of this disorder is autosomal recessive.
METHODS: We report a case of 4.11-year-old boy, of Arab-Muslim origin, living in an Arab town in Israel who presented at the age of 2 days with severe anemia, reticulocytosis, and leukocytosis. Investigation for common causes of hemolytic anemia was negative (peripheral blood smear was normal, and he had a negative Coombs test, normal G6PD, and normal flow cytometry spherocytosis). The anemia worsened during the following days (hemoglobin (Hb): 7.2 g/dL) and he needed several blood transfusions. NGS (next-generation sequencing) gene panel analysis was performed.
RESULTS: In an NGS gene panel analysis for hereditary hemolytic anemias, we found a homozygotic change in the GCLC gene-G53.385.643c379C > T(homo)pArg127Cys-which confirms the diagnosis of gamma-glutamylcysteine synthetase deficiency. An additional rare change was found in this case in the GCLC gene, with unknown clinical significance: g.53373917, c 828 + 3A > G. Except for chronic anemia (Hb levels around 8 g/dL), the child has normal physical and neurological development.
CONCLUSIONS: This study reports a rare case of gamma-glutamylcysteine synthetase deficiency in a 4.11-year-old Arab-Muslim boy from Israel who presented with severe anemia at 2 days old, aiming to document the first such case in the Middle East and contribute to the medical literature on this extremely rare condition that has only been detected in nine patients worldwide. Genetic analysis revealed a homozygotic change in the GCLC gene, confirming the diagnosis, and while the patient experiences chronic anemia, he maintains normal physical and neurological development, adding valuable insights to the understanding of this rare genetic disorder. An additional rare change was found in this case in the GCLC gene, with unknown clinical significance: g.53373917, c 828 + 3A > G.

Keywords: Arab-Muslim; autosomal recessive; consanguinity; enzymopathy; gamma-glutamylcysteine synthetase deficiency; glutathione synthesis disorder; hemolytic anemia

DOI: https://doi.org/10.3390/hematolrep17020020

Ann Hematol. 2025 Apr 25.

Decoding HbF reactivation by hydroxyurea in hemoglobinopathy patients through microRNA signatures.

Neha Kargutkar, Anita Nadkarni.

Hydroxyurea promotes HbF elevation in b-thalassemia and sickle cell anemia patients however, its mechanism is not completely elucidated. Previous studies have associated microRNAs with the regulation of HBG2, prompting this study to investigate specific microRNAs linked to HbF regulation in patients treated with hydroxyurea. 150 patients were recruited in the study. miRNA microarray panel of 754 miRNAs was used, and a further customised microarray card was designed. In silico tools predicted target genes of miRNAs and in vitro transfection functionally validated miRNAs in erythroblast cells from patients and K562 cells. Global microarray revealed 59 differentially expressed miRNAs, with 42 upregulated and 17 downregulated significantly following 3/6 months of hydroxyurea treatment (p < 0.001). Further, the customised miRNA panel of these 59 miRNAs confirmed the results. Among 59 miRNAs, 12 upregulated and 3 downregulated miRNAs correlated with HBG2 expression and HbF levels. In silico predictions and in vitro cells study identified miR-150, miR-155, miR-374, miR-486-3p (BCL11A, MYB); miR-190, miR-26a, miR-30b, miR-362, miR-411 (BCL11A); miR-192, miR-454 (MYB); miR-326 (KLF1); miR-150 (GATA1) and miR-15a, miR-484, miR-105 commonly share BCL11A, MYB, KLF1 and GATA1. Our study uncovers how microRNAs influence fetal hemoglobin induction in patients with hydroxyurea treatment, thus offering insights for developing treatment strategies and alleviating clinical severity.

Keywords: HbF; Hydroxyurea; Sickle cell anemia; Thalassemia; miRNA

DOI: https://doi.org/10.1007/s00277-025-06252-x

Int J Clin Pharmacol Ther. 2025 Apr 22.

Severe autoimmune hemolytic anemia associated with glucose-6-phosphate dehydrogenase deficiency as a complication of nivolumab treatment: A case report.

Roberto Lozano, María-Esther Franco, Carina Bona.

In recent years, immune checkpoint inhibitors, such as programmed death-1 (PD-1) inhibitors, have become key therapeutic options for specific cancers, used as first-, second-, or third-line treatments for various metastatic conditions. Nivolumab, a programmed death-1 (PD-1) inhibitor, is FDA-approved for metastatic renal cell carcinoma among other cancers. As the use of nivolumab becomes more widespread, understanding both its common and rare side effects is essential. Although nivolumab has been associated with autoimmune hemolytic anemia (AIHA), there are rare cases where this adverse effect may be compounded by other underlying conditions. Here, we report the first case of AIHA in a patient with glucose-6-phosphate dehydrogenase deficiency, triggered as a complication of nivolumab treatment.

DOI: https://doi.org/10.5414/CP204756