bims-sicedi Biomed News
on Sickle cell disease
Issue of 2025–03–02
eight papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo
  1. Gene therapy for sickle cell disease and thalassemia.
  2. Phenotype of sickle cell disease. Correlation of haplotypes and polymorphisms in cluster β, BCL11A, and HBS1L-MYB. Pilot study.
  3. A roadmap for uniform comprehensive long- term follow up after curative therapy for sickle cell disease.
  4. Megakaryocytes transfer mitochondria to bone marrow mesenchymal stromal cells to lower platelet activation.
  5. Haploidentical Bone Marrow Transplantation for Sickle Cell Disease.
  6. Cures for Sickle Cell Abound - How about Access?
  7. Histomorphology of placentae of women with sickle cell disease during pregnancy - A case control study.
  8. PREGNANCY OUTCOMES IN WOMEN WITH SICKLE CELL DISEASE AT A TERTIARY HOSPITAL IN NIGERIA: A FIVE-YEAR RETROSPECTIVE STUDY.
  1. Curr Opin Hematol. 2025 Feb 28.
    Gene therapy for sickle cell disease and thalassemia.
    Natalia Scaramellini, Daniele Lello Panzieri, Maria Domenica Cappellini.
       PURPOSE OF REVIEW: Thalassemia and sickle cell disease are among the most frequent monogenic hereditary diseases. Access to transfusions, iron chelation therapies and drugs such as hydroxyurea have improved life expectancy and quality of life. However, these diseases still cause significant disability. The first available curative therapy, bone marrow transplantation, is unfortunately not feasible for all patients. Over the past decade, numerous studies have focused on finding new curative therapies, and many clinical trials have evaluated different gene therapy approaches.
    RECENT FINDINGS: The therapeutic targets focus on adding functional copies of the gene encoding β-globin in defective CD34+ cells, mainly using lentiviral vectors directed towards HSCs. More recently, the focus has shifted to inducing fetal hemoglobin production at therapeutic levels or repairing the underlying molecular defect, using novel gene editing techniques involving CRISPR-Cas9, transcription activation-like effector protein nucleases, zinc finger nucleases and base editing. Preclinical and clinical studies now focus on optimizing how gene therapy is performed and delivered to reduce or eliminate myeloablative treatment and its potential adverse events.
    SUMMARY: In this review, we explore the potential to induce fetal hemoglobin production at therapeutic levels or to repair the underlying molecular defect that causes the disease genetically. Here, we review recent gene editing studies that are opening a new era in curative treatment for hemoglobinopathies.
    DOI:  https://doi.org/10.1097/MOH.0000000000000867
  2. Front Med (Lausanne). 2025 ;12 1347026
    Phenotype of sickle cell disease. Correlation of haplotypes and polymorphisms in cluster β, BCL11A, and HBS1L-MYB. Pilot study.
    Paloma Ropero, Miriam Peral, Luis Javier Sánchez-Martínez, Sara Rochas, Miguel Gómez-Álvarez, Jorge M Nieto, Fernando A González, Ana Villegas, Celina Benavente.
       Objective/Background: Sickle cell disease (SCD) is a monogenic disease with a highly variable phenotype depending on the amount of fetal hemoglobin (HbF), the main modulator. Variation of HbF levels among patients is genetically regulated. HbF determines both the phenotype of the disease and the response to treatment with the main drug used, hydroxyurea. The efforts of the researchers have focused on discovering the genetic factors responsible for HbF variation, mainly describing the haplotypes of the β cluster and single nucleotide polymorphisms (SNPs) at three different loci: BCL11A, HBS1L-MYB, and the β-globin cluster. This study aimed to determine the possible correlation between the number of SNPs and haplotypes with higher HbF levels in a cohort of patients with SCD. A positive association could explain why certain haplotypes, such as Senegal or Arab-Indian, show higher HbF levels and less severe disease.
    Methods: To test this hypothesis, the characterization of haplotypes was performed using the PCR-RFLP technique and genotyping of three SNPs representative of the three loci with the greatest association with HbF variation: XmnI (rs7482144), BCL11A (rs4671393), and HBS1L-MYB (rs9376092).
    Results: We found more SNPs in haplotypes related to higher HbF than those with less HbF, although only the SNP XmnI (rs7482144) showed a statistically significant association.
    Conclusion: We found a direct correlation between haplotypes and the number of SNPs. Haplotypes with higher levels of HbF and less severe phenotypes showed a higher number of SNPs. Thus, the Benin and Bantu haplotypes traditionally associated with poor prognosis showed the fewest mutated SNPs.
    Keywords:  BCL11A; HBS1L-MYB; XmnI; cluster haplotypes β; fetal hemoglobin; sickle cell disease
    DOI:  https://doi.org/10.3389/fmed.2025.1347026
  3. Blood Adv. 2025 Feb 24. pii: bloodadvances.2024013953. [Epub ahead of print]
    A roadmap for uniform comprehensive long- term follow up after curative therapy for sickle cell disease.
    Shalini Shenoy, Julie Kanter, Adetola A Kassim, Courtney D Fitzhugh, Elizabeth O Stenger, Monica Bhatia, Lydia H Pecker, Lakshmanan Krishnamurti, Allison A King.
      An increasing number of allogeneic transplant and autologous gene modification transplant therapies seek to eradicate sickle hemoglobin and the consequent hemolysis, vasculopathy, functional compromise, morbidity and mortality. As these modalities are used in parallel, it is important to be able to define the spectrum and stability of correction, long-term effects, and the pros and cons of each modality. A comparison between interventions that will be sought by providers and patients undergoing intervention require uniform assessments that evaluate disease-related and intervention-related effects for informed decision-making. This expert summary provides a pathway to functional evaluations with timing recommendations, provides broad management guidelines, and touches upon ongoing research efforts in the field. The roadmap of long-term follow-up can help clinicians and researchers choose assessments and time them in comparable fashion between the various transformative therapy efforts.
    DOI:  https://doi.org/10.1182/bloodadvances.2024013953
  4. J Clin Invest. 2025 Feb 27. pii: e189801. [Epub ahead of print]
    Megakaryocytes transfer mitochondria to bone marrow mesenchymal stromal cells to lower platelet activation.
    Chengjie Gao, Yitian Dai, Paul A Spezza, Paul Boasiako, Alice Tang, Giselle Rasquinha, Hui Zhong, Bojing Shao, Yunfeng Liu, Patricia A Shi, Cheryl A Lobo, Xiuli An, Anqi Guo, William B Mitchell, Deepa Manwani, Karina Yazdanbakhsh, Avital Mendelson.
      Newly produced platelets acquire a low activation state but whether the megakaryocyte plays a role in this outcome has not been fully uncovered. Mesenchymal stem cells (MSCs) were previously shown to promote platelet production and lower platelet activation. We found healthy megakaryocytes transfer mitochondria to MSCs mediated by Connexin 43 (Cx43) gap junctions on MSCs, which leads to platelets at a low energetic state with increased LYN activation, characteristic of resting platelets. On the contrary, MSCs have a limited ability to transfer mitochondria to megakaryocytes. Sickle cell disease (SCD) is characterized by hemolytic anemia and results in heightened platelet activation, contributing to numerous disease complications. Platelets in SCD mice and human patient samples had a heightened energetic state with increased glycolysis. MSC exposure to heme in SCD led to decreased Cx43 expression and a reduced ability to uptake mitochondria from megakaryocytes. This prevented LYN activation in platelets and contributed to increased platelet activation at steady state. Altogether, our findings demonstrate an effect of hemolysis in the microenvironment leading to increased platelet activation in SCD. These findings have the potential to inspire new therapeutic targets to relieve thrombosis-related complications of SCD and other hemolytic conditions.
    Keywords:  Bone marrow; Hematology; Mouse stem cells; Platelets; Stem cells
    DOI:  https://doi.org/10.1172/JCI189801
  5. NEJM Evid. 2025 Mar;4(3): EVIDoa2400192
    Haploidentical Bone Marrow Transplantation for Sickle Cell Disease.
    Adetola A Kassim, Mark C Walters, Mary Eapen, Madoc Smith, Brent R Logan, Melhem Solh, Christopher McKinney, Michael Nieder, Maureen Ross, Michael Kent, Ghada A Abusin, Kanwaldeep Mallhi, Jorge Galvez Silva, Paul Shaughnessy, Julie Kanter, Hilary Haines, Rafic Farah, Yasser A Khaled, Nicole Ritzau, Adam Mendizabal, Allistair Abraham, Catherine Bollard, Kenneth Cooke, Josu de la Fuente, Rabi Hanna, Mary M Horowitz, Lori C Jordan, Nitya Bakshi, Lakshmanan Krishnamurti, Eric Leifer, Kris Michael Mahadeo, Shalini Shenoy, Richard J Jones, Michael R DeBaun, Robert A Brodsky.
       BACKGROUND: Related human leukocyte antigen (HLA)-haploidentical bone marrow transplantation (BMT) with posttransplant cyclophosphamide may be curative for sickle cell disease. However, graft failure, severe graft-versus-host disease (GVHD), infections, and mortality remain a concern. We evaluated a novel conditioning regimen followed by related HLA-haploidentical BMT in adults with sickle cell disease.
    METHODS: In a phase 2, open-label, single-arm, multicenter study, 54 eligible participants from 19 U.S. centers were enrolled. Of these, 42 (78%) received transplantation with conditioning including antithymocyte globulin, fludarabine, cyclophosphamide, thiotepa, and total body irradiation. GVHD prophylaxis included posttransplant cyclophosphamide, mycophenolate mofetil, and sirolimus. The primary outcome was event-free survival at 2 years, while secondary outcomes included overall survival and other transplant-related end points.
    RESULTS: The median age at enrollment was 22.8 years (range, 15.5 to 43.2), and the median follow-up period was 37.2 months (range, 20.4 to 56.4). The 2-year event-free and overall survival rates were 88.0% (95% confidence interval [CI], 73.5 to 94.8%) and 95.0% (95% CI, 81.5 to 98.7%), respectively. Two participants experienced primary and another secondary graft failure. The incidence of grade-3-to-4 acute GVHD at day 100 was 4.8% (95% CI, 0.9 to 14.4%), while the 2-year chronic GVHD rate was 22.4% (95% CI, 10.9 to 36.4%). Two of the four reported deaths were due to early infectious complications.
    CONCLUSIONS: HLA-haploidentical BMT is an accessible and potentially curative therapy for adults with sickle cell disease. Adverse events were those anticipated from this procedure, including GVHD. (Funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute; BMT CTN 1507; ClinicalTrials.gov number, NCT03263559).
    DOI:  https://doi.org/10.1056/EVIDoa2400192
  6. NEJM Evid. 2025 Mar;4(3): EVIDe2400428
    Cures for Sickle Cell Abound - How about Access?
    Sanghee Hong, Mitchell E Horwitz.
      
    DOI:  https://doi.org/10.1056/EVIDe2400428
  7. PLoS One. 2025 ;20(2): e0319011
    Histomorphology of placentae of women with sickle cell disease during pregnancy - A case control study.
    Mohammed Mumuni, Kevin Kofi Adutwum-Ofosu, Benjamin Arko-Boham, Bismarck Afedo Hottor, Nii Koney-Kwaku Koney, Kwame Adu-Bonsaffoh, Samuel Antwi Oppong, Peter Ofori Appiah, John Ahenkorah.
       BACKGROUND: Sickle cell disease (SCD) is known to exert multifaceted effects on pregnancy, potentially influencing placental structure and function.
    AIM: Our aim was to utilize stereology as a precise analytical tool to evaluate the histo-morphologic and functional changes in term placentae of women with SCD against those of non-SCD women.
    METHOD: A case control study was conducted at the Korle-Bu Teaching Hospital's labour unit and included 38 pregnant women, comprising 19 cases and 19 controls. Placenta samples were paired and matched with gestational age and taken at term (38 weeks + 2 weeks). Tissue sections were prepared, stained with hematoxylin and eosin, and volume densities of syncytial knots, foetal capillaries, syncytial denuded areas, and intervillous spaces estimated by stereological methods. Statistical analysis was performed to compare mean values between the SCD and control groups.
    RESULTS: Among the study participants with SCD, 13.16% (5) had sickle cell haemoglobin S (HbSS), 34.21% (13) had haemoglobin C (HbSC) and 2.63% (1) had β-thalassemia (HbS). On stereological assessment, there were statistically significant differences in mean volume densities of syncytial knots (p = < 0.0034), foetal capillaries (p = < 0.0001), syncytial denudations (p = < 0.0028), and intervillous space (p = < 0.0113) between term placentae of women with SCD and those without SCD.
    CONCLUSION: SCD placentae may result in a substantial increase in syncytial knot formation, possibly because of hypermaturation of the chorionic villi, significant increase in foetal capillaries potentially due to the hypoxic nature of the SCD placentae, syncytial denuded areas as a result of alteration of the placental syncytium and reduced intervillous spaces which may be due to villous congestion. These findings suggest the need for heightened monitoring of placental function and fetal well-being in pregnancies complicated by SCD to reduce adverse perinatal outcomes.
    DOI:  https://doi.org/10.1371/journal.pone.0319011
  8. Ann Ib Postgrad Med. 2024 Aug 30. 22(2): 18-25
    PREGNANCY OUTCOMES IN WOMEN WITH SICKLE CELL DISEASE AT A TERTIARY HOSPITAL IN NIGERIA: A FIVE-YEAR RETROSPECTIVE STUDY.
    T A Olukunle, O O Ogunbode, R A Abdus-Salam.
       Background: Sickle cell disease (SCD) in pregnancy constitutes a high-risk pregnancy, associated with increased risk of adverse outcomes.
    Objective: To describe the outcome of pregnancy in SCD women managed at the University College Hospital, Ibadan, Nigeria.
    Materials and Methods: A retrospective review of the health records of sixty-three SCD pregnant women managed between January 1, 2016 and December 31, 2020. The information extracted included sociodemographic and obstetric characteristics, clinical presentations, mode of delivery, maternal and fetal outcomes. The data was analyzed using the IBM Statistical SPSS Statistics for Windows, version 23.0. Test of association was done using Chi-square and level of significance was p<0.05.
    Results: Prevalence of SCD in pregnant women was 0.65%. Mean age was 28.8±4.1years, 63.5% were haemoglobin SS while 36.5% were haemoglobin SC. Most of the women had tertiary education (61.8%) and booked for antenatal care (ANC) (60%). About 72.4% delivered at term while 46.1% had caesarean delivery. Most common complication was anaemia (79.4%) while vaso-occlusive crisis was the most common type of crisis (55.6%). Most of the women (92.5%) had live-birth with 15.2% of neonates requiring Neonatal Intensive Care Unit (NICU) admission. Maternal death rate was 6.3%. Good maternal and fetal outcomes occurred in 71.4% and 61.9% of participants respectively. Good maternal outcome was significantly associated with tertiary education(p=0.01). Good fetal outcome was associated with tertiary level of education(p=0.04) and multigravida status(p=0.03).
    Conclusion: SCD pregnant women have good fetal-maternal outcomes, however not receiving ANC and lower level of education were associated with poor pregnancy outcomes. Health education, access to ANC, prompt diagnosis, treatment of complications and multi-disciplinary team management will improve the pregnancy outcomes.
    Keywords:  Fetal outcome; Haemoglobinopathy; Maternal outcome; Sickle cell disease in pregnancy.
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