bims-sicedi 2024-11-17 papers

bims-sicedi

Biomed News

on Sickle cell disease

Issue of 2024–11–17
thirteen papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo

Promising role of Voxelotor in managing sickle cell disease in children: a narrative review.
Crispr-based gene therapy for the induction of fetal hemoglobin in sickle cell disease.
Discovery and Optimization of First-in-Class Molecular Glue Degraders of the WIZ Transcription Factor for Fetal Hemoglobin Induction to Treat Sickle Cell Disease.
The Current Role of Hydroxyurea in the Treatment of Sickle Cell Anemia.
Genetic Polymorphisms Associated with Fetal Hemoglobin (HbF) Levels and F-Cell Numbers: A Systematic Review of Genome-Wide Association Studies.
Globalization in clinical drug development for sickle cell disease.
Whole Blood Transcriptome Analysis in Congenital Anemia Patients.
The pattern of renal artery Doppler indices in patients with sickle cell disease.
Enhanced Vasoconstriction in Sickle Cell Disease is Dependent on ETA Receptor Activation.
Exploring machine learning algorithms in sickle cell disease patient data: A systematic review.
Determination of the Level of von Willebrand Factor, ADAMTS13, and Ratio of ADAMTS13:von Willebrand Factor in Sickle Cell Disease Patients.
Associations of haematological and inflammatory biomarkers with brain volume in patients with sickle cell anaemia: A cross-sectional retrospective study.
Prevalence and predictors of Sickle Cell Nephropathy A single-center experience.

Clin Exp Pediatr. 2024 Nov 13.

Promising role of Voxelotor in managing sickle cell disease in children: a narrative review.

Amit Agrawal, Gaurav Jadon, Japna Singh, Dalwinder Janjua.

  Sickle cell disease (SCD) is characterized by chronic hemolytic anemia and intermittent vaso-occlusive crises. To date, four disease-modifying drugs have been approved for the treatment of SCD: hydroxyurea (an S-phase inhibitor), L-glutamine (an amino acid), crizanlizumab (a P-selectin inhibitor), and voxelotor (a hemoglobin S polymerization inhibitor). Preclinical studies suggested that voxelotor effectively treats SCD and sickle cell anemia (SCA). In a phase III trial, voxelotor-treated patients showed significantly elevated hemoglobin levels (>1 g/dL from baseline) compared to placebo-treated patients. The group that received voxelotor also showed a greater decrease in hemolytic markers but a comparable incidence of side effects. Six ongoing clinical trials also sought to ascertain the effectiveness and safety of high-dose voxelotor when administered to children younger than 12 years. Studies assessing their long-term efficacy and safety are needed to fully understand the role of voxelotor in treating SCD/SCA. In this review, we discuss the mechanisms, trials to date, and future treatment directions of voxelotor.

Keywords:  Pharmacodynamics; Pharmacokinetics; Safety; Sickle cell anemia; Sickle cell disease; Voxelotor

DOI:  https://doi.org/10.3345/cep.2024.00500
Expert Rev Hematol. 2024 Nov 13.

Crispr-based gene therapy for the induction of fetal hemoglobin in sickle cell disease.

Meghann McManus, Haydar Frangoul, Martin H Steinberg.

   INTRODUCTION: Sickle cell disease is ameliorated, and perhaps can be 'cured' if enough fetal hemoglobin is present in most erythrocytes. Hydroxyurea, which increases fetal hemoglobin levels, is widely available and effective, especially in children. Nevertheless, only cell-based gene therapy can achieve a 'curative' fetal hemoglobin threshold.
AREAS COVERED: We cover the path to modulating fetal hemoglobin gene expression and the use of CRISPR/Cas9 gene editing as a viable clinical modality for treating severe sickle cell disease relying on references obtained from PubMed. Mobilized autologous hematopoietic stem and progenitor cells are engineered with vectors that derepress genes that regulate fetal hemoglobin gene expression. Following myeloablative conditioning gene-edited cells are reinfused, engraft, and make large amounts of fetal hemoglobin. Within months, fetal hemoglobin forms more than 40% of total hemoglobin and hemoglobin levels normalize; symptoms of sickle cell disease disappear.
EXPERT OPINION: Optimistically, these patients are 'cured,' but long term follow up is needed. Although approved by regulatory agencies and highly efficacious, because of its technical imperatives and cost this first gene editing therapeutic will be unavailable to most people with severe sickle cell disease. It is highly likely that improved methods of genomic editing will simplify gene therapy, reduce its costs, and lead to its wider applicability.

Keywords:  BCL11A gene; CRISPR/Cas9; fetal hemoglobin; gene editing; hemolytic anemia; sickle cell disease

DOI:  https://doi.org/10.1080/17474086.2024.2429605
J Med Chem. 2024 Nov 14.

Discovery and Optimization of First-in-Class Molecular Glue Degraders of the WIZ Transcription Factor for Fetal Hemoglobin Induction to Treat Sickle Cell Disease.

John Ryan Kerrigan, Noel M Thomsen, Artiom Cernijenko, Sarah E Kochanek, Janetta Dewhurst, Gary O'Brien, Nathaniel F Ware, Carina C Sanchez, James R Manning, Xiaolei Ma, Elizabeth Ornelas, Nikolas A Savage, James R Partridge, Andrew W Patterson, Philip Lam, Natalie A Dales, Simone Bonazzi, Sneha Borikar, Amelia E Hinman, Pamela Y Ting.

Sickle cell disease (SCD) is a prevalent, life-threatening condition with few treatment options, attributed to a heritable mutation in β-hemoglobin. Therapeutic induction of fetal hemoglobin (HbF) with small molecules has been pursued as a treatment to ameliorate many disease complications but with limited success. Herein, we report the discovery of 10, a novel, potent, and selective molecular glue degrader of the transcription factor WIZ that robustly induces HbF expression as a potential treatment for SCD. 10 was optimized from a phenotypic screening hit utilizing insights from X-ray crystallography and computational modeling to improve potency, selectivity and in vivo exposure. In an hNBSGW mouse xenograft model, 10 demonstrated robust WIZ degradation and HbF induction. These results highlight the potential of WIZ degraders as a promising therapy for sickle cell disease.

DOI: https://doi.org/10.1021/acs.jmedchem.4c02251
J Clin Med. 2024 Oct 25. pii: 6404. [Epub ahead of print]13(21):

The Current Role of Hydroxyurea in the Treatment of Sickle Cell Anemia.

Montserrat López Rubio, María Argüello Marina.

  Despite advancements in treatment of sickle cell disease (SCD), hydroxyurea, a ribonucleotide reductase inhibitor, remains the cornerstone of therapy. While its primary effect is the elevation of fetal hemoglobin (HbF), hydroxyurea's mechanisms of action are multifaceted. Hydroxyurea (HU) reduces leukocyte and platelet counts, decreases the expression of endothelial adhesion molecules CD36 and CD49d, and increases nitric oxide and cyclic nucleotide levels, which may facilitate vascular dilation and further HbF induction. Numerous studies have demonstrated that hydroxyurea therapy reduces the frequency of painful episodes, acute chest syndrome, and the need for erythrocyte transfusions and hospitalizations. Long-term use of hydroxyurea leads to reduced morbidity and mortality. Hydroxyurea should be initiated in children from 9 months of age, including asymptomatic individuals, and is recommended for adults experiencing pain crises that significantly interfere with daily activities or quality of life, as well as those with severe or recurrent vaso-occlusive crises, ACS, or severe symptomatic anemia. Hydroxyurea is not recommended during pregnancy or lactation due to potential teratogenic effects and transfer into breast milk. However, its use may be considered in high-risk patients, particularly during the second and third trimesters. Concerns about secondary tumor development have not been substantiated in long-term follow-up studies. Alternative therapies, including L-glutamine, crizanlizumab, and voxelotor, are not presently approved or available for clinical use in Europe.

Keywords:  breastfeeding; hydroxycarbamide; hydroxyurea; oncogenic effects; pregnancy; sickle cell anemia; sickle cell disease

DOI:  https://doi.org/10.3390/jcm13216404
Int J Mol Sci. 2024 Oct 23. pii: 11408. [Epub ahead of print]25(21):

Genetic Polymorphisms Associated with Fetal Hemoglobin (HbF) Levels and F-Cell Numbers: A Systematic Review of Genome-Wide Association Studies.

International Hemoglobinopathy Research Network (INHERENT)

  Elevated fetal hemoglobin (HbF), which is partly controlled by genetic modifiers, ameliorates disease severity in β hemoglobinopathies. Understanding the genetic basis of this trait holds great promise for personalized therapeutic approaches. PubMed, MedRxiv, and the GWAS Catalog were searched up to May 2024 to identify eligible GWAS studies following PRISMA guidelines. Four independent reviewers screened, extracted, and synthesized data using narrative and descriptive methods. Study quality was assessed using a modified version of the Q-Genie tool. Pathway enrichment analysis was conducted on gene lists derived from the selected GWAS studies. Out of 113 initially screened studies, 62 underwent full-text review, and 16 met the inclusion criteria for quality assessment and data synthesis. A total of 939 significant SNP-trait associations (p-value < 1 × 10-5) were identified, mapping to 133 genes (23 with overlapping variant positions) and 103 intergenic sequences. Most SNP-trait associations converged around BCL11A (chr.2), HBS1L-MYB, (chr.6), olfactory receptor and beta globin (HBB) gene clusters (chr.11), with less frequent loci including FHIT (chr.3), ALDH8A1, BACH2, RPS6KA2, SGK1 (chr.6), JAZF1 (chr.7), MMP26 (chr.11), COCH (chr.14), ABCC1 (chr.16), CTC1, PFAS (chr.17), GCDH, KLF1, NFIX, and ZBTB7A (chr.19). Pathway analysis highlighted Gene Ontology (GO) terms and pathways related to olfaction, hemoglobin and haptoglobin binding, and oxygen carrier activity. This systematic review confirms established genetic modifiers of HbF level, while highlighting less frequently associated loci as promising areas for further research. Expanding research across ethnic populations is essential for advancing personalized therapies and enhancing outcomes for individuals with sickle cell disease or β-thalassemia.

Keywords:  F cells; GWAS; SNP; beta thalassemia; fetal hemoglobin (HbF); genetic modifier; sickle cell disease (SCD); systematic review

DOI:  https://doi.org/10.3390/ijms252111408
Am J Hematol. 2024 Nov 12.

Globalization in clinical drug development for sickle cell disease.

Enrico Costa, Russell E Ware, Léon Tshilolo, Julie Makani, Hubert G M Leufkens, Lucio Luzzatto.

DOI: https://doi.org/10.1002/ajh.27525
Int J Mol Sci. 2024 Oct 31. pii: 11706. [Epub ahead of print]25(21):

Whole Blood Transcriptome Analysis in Congenital Anemia Patients.

Maria Sanchez-Villalobos, Eulalia Campos Baños, Elena Martínez-Balsalobre, Veronica Navarro-Ramirez, María Asunción Beltrán Videla, Miriam Pinilla, Encarna Guillén-Navarro, Eduardo Salido-Fierrez, Ana Belén Pérez-Oliva.

  Congenital anemias include a broad range of disorders marked by inherent abnormalities in red blood cells. These abnormalities include enzymatic, membrane, and congenital defects in erythropoiesis, as well as hemoglobinopathies such as sickle cell disease and thalassemia. These conditions range in presentation from asymptomatic cases to those requiring frequent blood transfusions, exhibiting phenotypic heterogeneity and different degrees of severity. Despite understanding their different etiologies, all of them have a common pathophysiological origin with congenital defects of erythropoiesis. We can find different types, from congenital sideroblastic anemia (CSA), which is a bone marrow failure anemia, to hemoglobinopathies as sickle cell disease and thalassemia, with a higher prevalence and clinical impact. Recent efforts have focused on understanding erythropoiesis dysfunction in these anemias but, so far, deep gene sequencing analysis comparing all of them has not been performed. Our study used Quant 3' mRNA-Sequencing to compare transcriptomic profiles of four sickle cell disease patients, ten thalassemia patients, and one rare case of SLC25A38 CSA. Our results showed clear differentiated gene map expressions in all of them with respect to healthy controls. Our study reveals that genes related to metabolic processes, membrane genes, and erythropoiesis are upregulated with respect to healthy controls in all pathologies studied except in the SLC25A38 CSA patient, who shows a unique gene expression pattern compared to the rest of the congenital anemias studied. Our analysis is the first that compares gene expression patterns across different congenital anemias to provide a broad spectrum of genes that could have clinical relevance in these pathologies.

Keywords:  blood disorders; congenital sideroblastic anemia (CSA); sickle cell disease (SCD); transcriptomic analysis; β-thalassemia

DOI:  https://doi.org/10.3390/ijms252111706
J Ultrason. 2024 Nov;24(97): 1-4

The pattern of renal artery Doppler indices in patients with sickle cell disease.

Vivek Patre, Nobal Chandrakar.

   Aim: To evaluate the pattern of renal artery Doppler indices in patients with sickle cell disease who do not have laboratory evidence of renal impairment.
Material and methods: A case-control study was carried out after enrolling 50 patients with sickle cell disease (HbSS phenotype) (sickle cell disease group) and 50 control subjects (control group). All the participants underwent ultrasound and color Doppler examination, and the pulsatility index and resistive index values of the main renal artery, segmental artery, and interlobar artery in both kidneys were recorded and compared.
Results: The Doppler measurements of the main renal artery, segmental artery, and interlobar artery were compared between the control and sickle cell disease groups. It was found that both pulsatility index and resistive index were significantly higher in the sickle cell disease group, as compared to the control group, for the main renal artery, segmental artery, and interlobar artery (p <0.0001, p <0.0001, and p <0.0001, respectively). The optimal cut-off points for mean pulsatility index and resistive index, as measured by the Youden index, were found to be >1.08 (72% sensitivity and 88% specificity) and >0.635 (66% sensitivity and 98% specificity), respectively.
Conclusions: Resistive index and pulsatility index values in renal Doppler sonography can serve as early radiologic predictors of renal vascular changes in sickle cell disease patients who do not have laboratory evidence of renal impairment.

Keywords:  pulsatility index (PI); renal artery Doppler; resistive index (RI); sickle cell disease

DOI:  https://doi.org/10.15557/jou.2024.0017
Clin Sci (Lond). 2024 Nov 11. pii: CS20240625. [Epub ahead of print]

Enhanced Vasoconstriction in Sickle Cell Disease is Dependent on ETA Receptor Activation.

John Miller Allan, Brandon M Fox, Malgorzata Kasztan, Gillian C Kelly, Patrick A Molina, McKenzi A King, Jackson Colson, Leigh Wells, Latanya Bowman, Marsha Blackburn, Abdullah Kutlar, Ryan A Harris, David M Pollock, Jennifer Pollock.

  Sickle Cell Disease (SCD) carries a significant risk for poor vascular health and vascular dysfunction. High levels of vascular reactive oxygen species (ROS) as well as elevated plasma endothelin-1 (ET-1), a potent vasoconstrictor with actions via the ETA receptor, are both common phenotypes in SCD. Alpha-1 adrenergic receptor activation is a major mediator of stress-induced vasoconstriction. However, the mechanism of the SCD enhanced vasoconstrictive response is unknown. We hypothesized that SCD induces enhanced alpha-1 adrenergic mediated vasoconstriction through the ET-1/ETA receptor pathway in arterial tissues. Utilizing humanized SCD (HbSS) and genetic control (HbAA) mice, alpha-1a, but not alpha-1b or alpha-1d, receptor expression was significantly greater in aortic tissue from HbSS mice compared to HbAA mice. Significantly enhanced vasoconstriction in aortic and carotid arterial segments were observed from HbSS mice compared to HbAA mice. Treatment with ambrisentan, a selective ETA receptor antagonist, and a ROS scavenger normalized the aortic vasoconstrictive response in HbSS mice. In a randomized translational study, patients with SCD were treated with placebo or ambrisentan for 3 months, with the treatment group showing an increase in the percent brachial arterial diameter. Taken together, these data suggest that the ETA receptor pathway interaction with the adrenergic receptor pathway contributes to enhanced aortic vasoconstriction in SCD. Findings indicate the potential of ETA antagonism as a therapeutic avenue for improving vascular health in SCD.

Keywords:  endothelin-1; sickle cell disease; vasoconstriction

DOI:  https://doi.org/10.1042/CS20240625
PLoS One. 2024 ;19(11): e0313315

Exploring machine learning algorithms in sickle cell disease patient data: A systematic review.

Tiago Fernandes Machado, Francisco das Chagas Barros Neto, Marilda de Souza Gonçalves, Cynara Gomes Barbosa, Marcos Ennes Barreto.

This systematic review explores the application of machine learning (ML) algorithms in sickle cell disease (SCD), focusing on diagnosis and several clinical characteristics, such as early detection of organ failure, identification of drug dosage, and classification of pain intensity. A comprehensive analysis of recent studies reveals promising results in using ML techniques for diagnosing and monitoring SCD. The review covers various ML algorithms, including Multilayer Perceptron, Support Vector Machine, Random Forest, Logistic Regression, Long short-term memory, Extreme Learning Machines, Convolutional Neural Networks, and Transfer Learning methods. Despite significant advances, challenges such as limited dataset sizes, interpretability concerns, and risks of overfitting are identified in studies. Future research directions entail addressing these limitations by harnessing larger and more representative datasets, enhancing model interpretability, and exploring advanced ML techniques like deep learning. Overall, this review underscores the transformative potential of ML in increasing the diagnosis, monitoring and define prognosis of sickle cell disease while also highlighting the need for further investigation in the field.

DOI: https://doi.org/10.1371/journal.pone.0313315
Ann Afr Med. 2024 Nov 08.

Determination of the Level of von Willebrand Factor, ADAMTS13, and Ratio of ADAMTS13:von Willebrand Factor in Sickle Cell Disease Patients.

Akaba Kingsley Onorhide, Akpan Samuel Idongesit, Osho Patrick Olanrewaju.

BACKGROUND: Sickle cell anemia (SCA) is a hypercoagulable state characterized by a significant alteration in hemostatic parameters which may predispose an increased risk of vaso-occlusive crisis (VOC). Sickle cell disease (SCD) is the most common genetic disorder in sub-Saharan Africa. Nigeria bears a high disease burden with an estimated prevalence of 1%-3% of its population being affected by the disease. The study seeks to determine the role of von Willebrand factor (VWF), ADAMTS13, and the ratio of ADAMTS13:VWF antigen in the pathogenesis of VOC.
OBJECTIVE: The objective of this study is to evaluate the level of VWF, ADAMTS13, and their ratio in SCD subjects in Calabar and to determine their role in the pathogenesis of VOC.
METHODOLOGY: This is a comparative study carried out at the University of Calabar Teaching Hospital (UCTH), Calabar. Sixty SCA patients were evaluated in VOC and steady states as well as five parented healthy controls. VWF: Ag and ADAMTS13:Ag were evaluated using Assaypro enzyme-linked immunosorbent assay kits with Lot nos. 01751728 and 04222167R, respectively. Data were analyzed by IBM SPSS Chicago software version 21. The study was approved by the UCTH Institution Ethical Review Board.
RESULTS: The mean ages of the SCA subjects and controls were 23.5 ± 7.2 years and 26.5 ± 5.6 years, respectively (P = 0.706). There were 23 (38.3%) males in the SCA group and 21 (42.0%) females in the controls. There was no significant difference in their sex distribution (P = 0.063). The mean (standard deviation [SD]) of VWF in VOC, steady state, and controls were 2.52 ± 0.34, 1.34 ± 0.23, and 1.41 ± 0.23 IU/mL, respectively. The differences in mean were significantly higher in VOC state (P = 0.003). The mean ± SD of ADAMTS13 in VOC, steady state, and controls were 0.61 ± 0.10, 0.44 ± 0.06, and 0.62 ± 0.10 μg/L, respectively. ADAMTS13 levels did not differ significantly across the groups (P = 0.270). Similarly, there was no significant difference between ADAMTS13:VWF ratios across the groups (P = 0.318).
CONCLUSION: VWF level is elevated in VOC state and thus may be implicated in the pathogenesis of VOC. ADAMTS13 and the ratio of ADAMTS13:VWF are not significantly affected in VOC.

DOI: https://doi.org/10.4103/aam.aam_25_22
Trop Med Int Health. 2024 Nov 07.

Associations of haematological and inflammatory biomarkers with brain volume in patients with sickle cell anaemia: A cross-sectional retrospective study.

Naif A Majrashi, Ali M Hendi, Turki M Dhayihi, Abdullah M Khamesi, Mohammed A Masmali, Khalid J Hakami, Ali S Alyami, Bandar Alwadani, Wael A Ageeli, Yahia Madkhali, Ali Hakamy, Turkey A Refaee.

  Sickle cell disease is a genetic disorder characterised by abnormal haemoglobin production. This study aims to investigate the associations between haematological and inflammatory biomarkers and brain volumes in patients with sickle cell anaemia and compare brain structure between patients with sickle cell anaemia and healthy controls. This retrospective cross-sectional study included 130 participants (70 sickle cell anaemia patients and 60 healthy controls) who underwent brain MRI examinations at King Fahad Central Hospital between January 2010 and October 2022. Demographic data and haematological and inflammatory biomarkers were collected to examine their relationships with brain volumes. Brain volumes were measured using FreeSurfer. Specific haematological and inflammatory biomarkers were correlated with brain volume in patients with sickle cell anaemia, p < 0.05. Sickle cell anaemia patients exhibited smaller volumes in the brainstem, corpus callosum and amygdala compared to healthy controls. Males had significantly higher iron levels (p < 0.001) and larger various brain structure volumes (p < 0.05) than females. This study demonstrates significant associations between specific biomarkers and brain volume in sickle cell anaemia patients, underscoring the importance of monitoring these biomarkers for early detection and management of neurological complications in sickle cell anaemia.

Keywords:  FreeSurfer; MRI; brain volume; cortical; haematological; inflammatory biomarkers; sickle cell anaemia

DOI:  https://doi.org/10.1111/tmi.14056
Sci Rep. 2024 Nov 15. 14(1): 28215

Prevalence and predictors of Sickle Cell Nephropathy A single-center experience.

Khaled Elzorkany, Mortadah Alsalman, Muthana AlSahlawi, Azam Alhedhod, Nasser Abdullah Almulhim, Nora Jalal Alsultan, Eman Mohammed Al-Ali, Eman Ali, Nawal Eltayeb Omer.

  Sickle cell disease (SCD) is the most common monogenic disorder in Saudi Arabia, which associates with an increased risk of organs damage, including the kidney. The aim of this study is to investigate the prevalence and predictors of sickle cell nephropathy (SCN) in the Saudi population. A retrospective study was conducted from April to October 2023, and included 343 adult patients with SCD who were recruited from the hereditary blood diseases center (HBDC), Al-Ahsa, Saudi Arabia. Spot protein-to-creatinine ratio was measured and glomerular filtration rate (GFR) was estimated from serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. As per KIDGO guidelines, CKD was diagnosed in 93 (27.1%) patients. Based on the CKD-EPI equation, 2% of patients had low GFR (eGFR < 60mL/min), 28.3% had high GFR (eGFR > 140 mL/min), and 69.7% had normal GFR. Among SCD patients, proteinuria was observed in 26.5% of the patients. SCD patients with CKD were significantly older than non-CKD patients (p < 0.001) and had higher prevalence of diabetes mellitus (DM) and hypertension (HTN) (p = 0.045 and 0.001 respectively). The multivariate analysis showed that age (P = 0.001; OR 1.035; 95% CI 1.014-1.056) and low hemoglobin level (p = 0.034; OR -0.851; 95% CI 0.721-0.980) were independent risk factors for the development of SCN. Nephropathy is a common complication among patients with SCD as early as the third decade of life, although they remain asymptomatic. Advances in age and low hemoglobin levels are the main predictors of nephropathy. In addition, SCD patients with coexistent comorbidities, particularly DM and HTN, were at increased risk of developing kidney disease.

Keywords:  CKD; Hydroxyurea; Sickle cell disease; sickle cell nephropathy

DOI:  https://doi.org/10.1038/s41598-024-79345-8