bims-sicedi 2025-03-16 papers

bims-sicedi

Biomed News

on Sickle cell disease

Issue of 2025–03–16
nine papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo

A critique review of fetal hemoglobin modulators through targeting epigenetic regulators for the treatment of sickle cell disease.
Accelerated Drug Approvals and Patient Trust: Impact of Voxelotor & Crizanlizumab for Sickle Cell Disease.
Soluble immune checkpoints are dysregulated in patients with sickle cell disease and correlate with inflammatory mediators, autoantibodies, immune cell profiles, and clinical outcomes.
Epidemiology of Intensive Care Use for Patients with Sickle Cell Disease in New York State.
A Controlled Trial for Preventing Priapism in Sickle Cell Anemia: Hydroxyurea plus Placebo vs Hydroxyurea plus Tadalafil.
Unraveling the multifaceted roles of peroxiredoxins in sickle cell anemia: implications in redox and inflammation adaptations.
Neurocognitive Gains Among Ugandan Children with Sickle Cell Anemia on Hydroxyurea: 18-month trial interim results.
High Mortality Due to Pneumococcal Meningitis in Children With Sickle Cell Disease: A French Multicenter Observational Study From 2001 to 2021.
The use of race and ethnicity in sickle cell disease research.

Life Sci. 2025 Mar 06. pii: S0024-3205(25)00170-5. [Epub ahead of print]369 123536

A critique review of fetal hemoglobin modulators through targeting epigenetic regulators for the treatment of sickle cell disease.

Chandu Ala, Sivaprakash Ramalingam, Chandra Sekhar Kondapalli Venkata Gowri, Murugesan Sankaranarayanan.

  Sickle cell disease (SCD) is one of the most prevalent hereditary blood disorders characterized by aberrant hemoglobin synthesis that causes red blood cells (RBCs) to sickle and result in vaso-occlusion. The complex pathophysiological mechanisms that underlie SCD are explored in this study, including hemoglobin polymerization, the formation of fetal hemoglobin (HbF), and hemoglobin switching regulation. Notably, pharmaceutical approaches like hydroxyurea, l-glutamine, voxelotor, and crizanlizumab, in addition to therapeutic techniques like gene therapies like Casgevy and Lyfgenia, signify noteworthy advancements in the management of issues connected to SCD. Furthermore, the deciphering of the molecular mechanisms that dictate hemoglobin switching has revealed several potentially therapeutic targets, including key transcriptional repressors such as β-cell lymphoma/leukemia 11A (BCL11A), Zinc finger and BTB domain-containing 7A (ZBTB7A), Nuclear Factor IX (NFIX), and Nuclear Factor IA (NFIA), which play crucial roles in γ-globin silencing. Additionally, transcriptional activators such as Nuclear Factor Y (NF-Y), and Hypoxia-inducible factor 1α (HIF1α) have emerged as promising regulators that can disrupt repression and enhance HbF synthesis. Other epigenetic regulators, such as lysine-specific histone demethylase 1 (LSD1), euchromatic histone methyltransferases 1/2 (EHMT1/2), histone deacetylases (HDACs), DNA methyltransferases (DNMTs), and protein arginine methyltransferases (PRMTs). It has been demonstrated that inhibiting these targets can prevent the silencing of the gene encoding for the formation of γ-chains and, in turn, increase the synthesis of HbF, providing a possible treatment option for SCD symptoms. These approaches could pave the way for innovative, mechanism-driven therapies that address the unmet medical needs of SCD patients.

Keywords:  Epigenetic regulators; Fetal hemoglobin; HbF induction; Red blood cells; Sickle cell disease

DOI:  https://doi.org/10.1016/j.lfs.2025.123536
Blood Adv. 2025 Mar 14. pii: bloodadvances.2025015822. [Epub ahead of print]

Accelerated Drug Approvals and Patient Trust: Impact of Voxelotor & Crizanlizumab for Sickle Cell Disease.

Kristine Anne Karkoska, Seethal A Jacob, Patrick T McGann.

Crizanlizumab and voxelotor were several of the first drugs to receive FDA approval for sickle cell disease (SCD) since the approval of hydroxyurea in 1998. Although initially exciting, additional data regarding efficacy and safety have since emerged for both drugs, first with the removal of crizanlizumab from the European market in August 2023. This was followed by Pfizer's abrupt decision in September 2024 to pull voxelotor from global markets due to higher mortality in those on the drug versus placebo. These drugs highlight the importance and limitations of the FDA accelerated approval process. In addition, the impact of these events, without transparent messaging, potentially threatened the fragile trust that providers have more recently been able to build with the SCD population regarding the medical system and research. While there is a need for new therapies in SCD, we must prioritize both safety and efficacy, and maintain trust in this population.

DOI: https://doi.org/10.1182/bloodadvances.2025015822
medRxiv. 2025 Feb 28. pii: 2025.02.27.25322979. [Epub ahead of print]

Soluble immune checkpoints are dysregulated in patients with sickle cell disease and correlate with inflammatory mediators, autoantibodies, immune cell profiles, and clinical outcomes.

Wei Li, Andrew Q Pucka, Lina Houran, Xiaoqing Huang, Candice Debats, Brandon A Reyes, Andrew Rw O'Brien, Qigui Yu, Ying Wang.

Background: Sickle cell disease (SCD) is a chronic condition characterized by inflammation, immune dysregulation, and debilitating pain.
Aim: This study investigates soluble immune checkpoints (sICPs) and their associations with inflammatory mediators, immune cell profiles, autoantibodies, and clinical outcomes in SCD.
Method: Peripheral blood samples from 50 SCD patients and 40 demographic-matched healthy controls (HCs) were analyzed for 37 sICPs, 80 inflammatory mediators, and 18 autoantibodies using multiplex assays, alongside immune cell profiles via flow cytometry. Pain and quality of life (QoL) were assessed through patient-reported outcome measures (PROMs).
Results: Twenty-three sICPs, including arginase-1, BTLA, CD27, CD28, CD47, CD80, CD96, CD134, CD137, CD152, GITR, HVEM, IDO, LAG-3, MICA, MICB, Nectin-2, PD-1, Siglec-7, Siglec-9, TIM-3, TIMD-4, and VISTA, were significantly elevated in SCD patients compared to HCs. These sICPs correlated with multiple proinflammatory mediators (e.g., IL-18), autoantibodies (e.g., MPO), and immune cell activation markers (e.g., CD38/HLA-DR on CD8 T cells). Notably, CD28, CD152, HVEM, and VISTA were strongly associated with systemic inflammation and immune cell activation, while BTLA, LAG-3, PD-1, and CD80 correlated with pain and anxiety scores and QoL.
Conclusion: This study highlights complex interactions between sICPs, immune activation, inflammation, and clinical outcomes in SCD, underscoring their potential as biomarkers or therapeutic targets to alleviate inflammation and improve QoL in this challenging clinical population.

DOI: https://doi.org/10.1101/2025.02.27.25322979
Chest. 2025 Mar 10. pii: S0012-3692(25)00278-8. [Epub ahead of print]

Epidemiology of Intensive Care Use for Patients with Sickle Cell Disease in New York State.

Miguel Eduardo Cid, Zhixin Yang, Jeffrey Glassberg, Sarah McCuskee, May Hua.

DOI: https://doi.org/10.1016/j.chest.2025.02.028
Blood. 2025 Mar 12. pii: blood.2024027898. [Epub ahead of print]

A Controlled Trial for Preventing Priapism in Sickle Cell Anemia: Hydroxyurea plus Placebo vs Hydroxyurea plus Tadalafil.

Ibrahim Musa Idris, Aminu Abba Yusuf, Ismail Isah Ismail, Awwal Musa Borodo, Mustapha Shuaibu Hikima, Shehu Abubakar Kana, Tukur Aliyu, Kabiru Musan Gedu, Atiku Usman Jibrillah, Sani Ali Aji, Aisha Kuliya-Gwarzo, Kabeer Bello Mohammed, Jamil A Galadanci, Rukayya Sunusi Alkassim, Mohammad Abba Suwaid, Nafiu Hussaini, Mark Rodeghier, Arthur Louis Burnett, Michael R DeBaun.

Recurrent ischemic priapism is a common complication of sickle cell anemia (SCA) and is associated with devastating physical and psychosocial consequences. All previous trials for priapism prevention have failed to demonstrate clear efficacy. We conducted a randomized, controlled, double-blind phase 2 feasibility trial comparing fixed moderate-dose hydroxyurea plus placebo (usual care arm) versus fixed moderate-dose hydroxyurea plus tadalafil (experimental arm) in 64 men (18- 40 years) with at least three episodes of SCA-related priapism in the past 12 months. Priapism data were obtained via daily text messages to the participants. The trial's primary outcome measures were 100% recruitment, 98.4% retention, and 93.5% adherence rates. Over a median of 10 months (IQR: 3-12), 2.5 and 3.02 priapism events per participant-month were recorded in the usual care and the experimental arms, with an incidence rate ratio of 0.8; 95% CI: 0.3 -1.9; p= 0.654. Serious adverse events (p=0.999) and hospitalizations (p=0.289) were similar in both arms. Sperm concentration, motility, and normal morphology significantly decreased on hydroxyurea therapy but recovered to pre-hydroxyurea levels three months after therapy cessation. Post-hoc, single-arm, pre- and post-analysis comparing the priapism rate in the treatment phase to pre-randomization showed a 58.3% priapism incidence rate reduction in the usual care arm (5.9 to 2.5 events per month; difference 3.4, 95% CI: 1.1 - 5.8; p=0.005]) and 66.3% priapism reduction in the experimental arm (8.9 to 3.02 events per month; difference 5.9; 95% CI: 3.4 - 8.5; p<0.001]). A randomized controlled trial for priapism prevention is feasible in men with SCA. (NCT05142254).

DOI: https://doi.org/10.1182/blood.2024027898
Ann Hematol. 2025 Mar 14.

Unraveling the multifaceted roles of peroxiredoxins in sickle cell anemia: implications in redox and inflammation adaptations.

Karen Simone Romanello, João Pedro Maia de Oliveira da Silva, Flaviene Felix Torres, Karina Kirschner Lopes Teixeira, Igor de Farias Domingos, Gabriela da Silva Arcanjo, Diego Antônio Pereira Martins, Aderson da Silva Araujo, Marcos André Cavalcanti Bezerra, Iran Malavazi, Danilo Grünig Humberto da Silva, Anderson Ferreira da Cunha.

  Sickle cell anemia (SCA) presents a complex interplay of factors, with the production of high levels of reactive oxygen species (ROS) and the chronic inflammatory process leading to chronic oxidative stress. In this context, efficient action of antioxidant systems becomes crucial, with particular emphasis on peroxiredoxins (PRDXs) due to their abundance and vital roles. Our primary objective was to establish associations between gene and protein expression of PRDXs 1, 2, and 6, as well as their reducers TRX1, TRXR1, and SRX1, with the characteristic hyperoxidative status observed in SCA patients. Concomitantly, we assessed the production of other essential antioxidant enzymes (SOD1, CAT, and GPX1) in reticulocytes and erythrocytes and explored mRNA levels of the NRF2/KEAP1/PKCδ complex. Our comprehensive analysis revealed a ∼ 3-fold elevation in ROS levels in erythrocytes of patients compared to healthy individuals. However, the NRF2/KEAP1/PKCδ complex exhibited a significant reduction in gene expression, hinting that another transcription factor may regulate the antioxidant response among SCA patients. In addition, the pattern of increased transcript levels of antioxidants in SCA patients was not associated with their protein levels, indicating a possible degradation by proteasome. The protein content of PRDX2 showed a significant reduction, indicating an increased vulnerability of these cells to oxidative damage. Intriguingly, both PRDXs 1 and 2 exhibited significant increases in the plasma of SCA patients, indicating that, besides their well-known intracellular antioxidant role, these enzymes may also play a vital extracellular role in modulating inflammation in these individuals. Our findings unveil novel insights into the redox metabolism adaption of erythroid cells in response to the presence of HbS in homozygosity, thus, into the complex SCA pathophysiology. Moreover, our study reveals the simultaneous presence of both PRDXs 1 and 2 in the plasma of these patients, thereby offering valuable implications for potential prognostic and therapeutic avenues.

Keywords:  Inflammation mediators; Oxidative stress; Peroxiredoxins; Proteasome

DOI:  https://doi.org/10.1007/s00277-025-06294-1
Blood Adv. 2025 Mar 14. pii: bloodadvances.2024015073. [Epub ahead of print]

Neurocognitive Gains Among Ugandan Children with Sickle Cell Anemia on Hydroxyurea: 18-month trial interim results.

Shubaya Kasule Naggayi, Dennis Kalibbala, Vincent Mboizi, John M Ssenkusu, Zhezhen Jin, Caterina Rosano, Deogratias Munube, Bill Wambaka, Ruth Namazzi, Phillip G Kasirye, Maxencia Kabatabaazi, Grace Nambatya, Susan Murungi, Catherine Nabaggala, Maria Rwiza Nakafeero, Ian R Troidl, Robert O Opoka, Richard Idro, Paul Bangirana, Nancy S Green.

Children with sickle cell anemia (SCA) frequently develop progressive neurocognitive impairment. We aimed to determine effects of hydroxyurea therapy on neurocognitive function in Ugandan children with SCA by comparing levels at enrollment to a planned 18-month interim assessment. Ugandan children (N=264) ages 3-9 years were enrolled from a SCA clinic and treated in a 30-month single-arm open-label trial with escalation to maximum tolerated dose (MTD). Primary outcome was the effects of hydroxyurea on cognition, attention and executive function, along with transcranial doppler ultrasound (TCD) blood flow velocity. Sibling controls (N=110) without SCA underwent neurocognitive testing in parallel to establish age-normalized z-scores for comparison. Participant enrollment mean age was 5.6±1.2 years, with comparable socio-economic status (SES) and caregiver education versus controls. At enrollment, SCA participants had lower mean cognitive z-scores than controls; 8.7% had cognitive impairment versus 1.6% controls. Month 18 mean dose 25.4mg/kg, with participants significantly improved z-scores versus baseline in all three domains: cognition: -0.54±1.10 vs. -0.07±1.16, p<0.001; attention: -0.07±1.01 vs. 0.27±0.84, p<0.001; and executive function: -0.06±0.62 vs. 0.08 ±0.72, p=0.010. No measure differed from controls. Proportion with SCA and cognitive impairment declined to 4.0%, with decreased mean TCD velocity. Higher neurocognitive treatment z-scores were primarily associated with higher baseline, also with better SES, hydroxyurea-induced TCD and hematological effects. Despite improvement, unadjusted cognitive scores remained negatively associated with age. Hydroxyurea therapy improved SCA neurocognitive function in sub-Saharan children, potentially aided by practice effects. Early treatment is needed for optimal effect. Our ongoing trial will assess impact from longer-term therapy. This trial was registered at www.clinicaltrials.gov as NCT04750707.

DOI: https://doi.org/10.1182/bloodadvances.2024015073
Pediatr Infect Dis J. 2025 Mar 07.

High Mortality Due to Pneumococcal Meningitis in Children With Sickle Cell Disease: A French Multicenter Observational Study From 2001 to 2021.

Inès Fafi, Robert Cohen, Corinne Levy, Emmanuelle Varon, Lahoueri Amor-Chelihi, Patricia Benhaim, Marine Houlier, Bérangère Koehl, Mariane De Montalembert, Slimane Allali, Alexandra Gauthier, Marie-Hélène Odièvre, Vincent Gajdos, Simon Escoda, Annie Kamdem, Guillaume Costa, Cécile Guillaumat, Isabelle Thuret, Naïm Ouldali, Jean Gaschignard, Etienne Carbonnelle, Loic De Pontual, Luu-Ly Pham.

BACKGROUND: Sickle cell disease (SCD) predisposes children to bacterial infections, particularly invasive pneumococcal disease. Pneumococcal immunization associated with antibiotic prophylaxis reduced the incidence of invasive pneumococcal disease in these patients. However, the risk remains higher than in the general population. Our main objective was to describe the features of pneumococcal meningitis and estimate the case-fatality rate in children with SCD. The secondary objective was to assess serotype distribution and resistance patterns and the proportion of cases related to vaccine failure.
METHODS: This nationwide multicenter observational study was conducted in France between 2001 and 2021. All cases of pneumococcal meningitis in children with SCD < 18 years old from the French National Registry of Pediatric Pneumococcal Meningitis were included.
RESULTS: Of 2145 pneumococcal meningitis, 25 cases (1.2%, 95% CI: 0.8-1.7) occurred in children with SCD [mean age = 4.6 years (±4)], with a high case-fatality rate (28%, n = 7, 95% CI: 10.4-45.6). Nonvaccine serotypes were predominant (n = 15, 65%, 95% CI: 45.8-84.7) over vaccine serotypes (n = 8, 35%, 95% CI: 15.3-54.3). One case of vaccine failure (4%, n = 1/23) and 2 breakthrough cases (n = 2/23, 9%) were observed. Penicillin-non-susceptible Streptococcus pneumoniae strains were identified in 39% (n = 7).
CONCLUSIONS: The occurrence of pneumococcal meningitis in children with SCD during the pneumococcal conjugate vaccines era was associated with a high case-fatality rate and a predominance of nonvaccine serotypes. The implementation of new serotype-expanded PCV may have a potentially positive impact on this vulnerable population.

DOI: https://doi.org/10.1097/INF.0000000000004755
BMC Med Res Methodol. 2025 Mar 07. 25(1): 63

The use of race and ethnicity in sickle cell disease research.

Aida S Kidane Gebremeskel, Minke A Rab, Erik D van Werkhoven, Teun B Petersen, Marjon H Cnossen, Amade M'charek, Karlijn A C Meeks, Anita W Rijneveld.

  This study explores practices surrounding the operationalization of ethno-racial categories (ERCs) as confounders in biomedical research, with a focus on sickle cell disease (SCD) as a model. ERCs, often aggregate labels encompassing diverse individuals which raises questions about their relevance as confounders. Given SCD's racialization as a "Black" disease, understanding ERC utilization is crucial. This study analyzed 1,105 SCD studies published globally. Data were collected on whether ERC adjustment was employed, regional variations in ERC-adjustment rates, labels used for ERCs, rationales provided for ERC matching, and methods used for ERC determination. 28% of the studies utilized ERC adjustment, with significant regional disparities (p < 0.001). Notably, Western studies showed higher rates of ERC adjustment compared to other regions. However, crucial details such as ERC labels and methodology were frequently missing. Commonly used labels included "African" or "Black." Only 7% of studies provided explicit rationales for ERC matching, and 70% did not specify the method used for ERC determination. The findings underscore the need to adhere to guidelines on ERC operationalization in biomedicine. The lack of standardized practices raises concerns about potential biases and misinterpretations in research outcomes. Adhering to clear guidelines can mitigate the risk of perpetuating racial stereotypes and inequalities while ensuring research integrity.

Keywords:  Confounder adjustment; Ethnicity; Ethno-racial categories; Race; Sickle cell disease

DOI:  https://doi.org/10.1186/s12874-025-02513-5