bims-conane 2024-07-07 papers

INTRODUCTION: Acute pain episodes, also known as vaso-occlusive crises (VOC), are a major symptom of sickle cell disease (SCD) and lead to frequent hospitalizations. The diagnosis of VOC can be challenging, particularly in adults with SCD, 50% of whom have chronic pain. Several potential biomarkers have been proposed for identifying individuals with VOC, including elevation above the baseline of various vascular growth factors, cytokines, and other markers of inflammation. However, none have been validated to date.
AREAS COVERED: We summarize prospective biomarkers for the diagnosis of acute pain in SCD, and how they may be involved in the pathophysiology of a VOC. Previous and current strategies for biomarker discovery, including the use of omics techniques, are discussed.
EXPERT OPINION: Implementing a multi-omics-based approach will facilitate the discovery of objective and validated biomarkers for acute pain.

Keywords: Acute pain; Pain; pain biomarkers; sickle cell disease; vaso-occlusive crisis

DOI: https://doi.org/10.1080/17474086.2024.2372322

Ghana Med J. 2023 Sep;57(3): 198-203

Plasma concentration of fucosyltransferase 7 is not associated with the number of clinically overt vaso-occlusive events in sickle cell disease.

Iheanyi E Okpala, Onyinye E Eze, Chinedu A Ezekekwu, Ifeyinwa D Nnakenyi, Gladys U Ilechukwu, Chinedu O Akpa, Emmanuel I Nwani, Collins J Maduka, Ikechukwu O Anigbogu, Ebele D Muoghalu, Ngozi I Ugwu, Ifeoma C Ajuba, John C Aneke, Helen C Okoye, Charles C Nonyelu, Augustine N Duru.

Objective: To determine if the number of vaso-occlusive events in SCD relates to plasma concentration of fucosyltransferase 7 (FUT7), which catalyses the synthesis of selectin ligands.
Design: A prospective, analytical study.
Setting: Haematology and Chemical Pathology Departments of tertiary healthcare centres.
Participants: Steady state HbSS individuals aged 13-45 years, 20 had 3 or more vaso-occlusive crises that required hospital admission in the previous year (with or without complications of SCD); 17 other HbSS persons had 0-1 vaso-occlusive crisis that required hospital admission in the previous year and no disease complications.
Intervention: Steady-state plasma concentrations of FUT7 measured by ELISA were compared between SCD patients who had one vaso-occlusive crisis requiring hospital treatment in the previous year but no disease complications and those who had >3 crises with or without complications.
Main Outcome Measures: Plasma level of FUT7and the number of vaso-occlusive events in each HbSS patient.
Results: Mean + standard deviation plasma concentration of FUT7 was 8.6 + 2.7 ng/ml in patients with >3 vasoocclusive crises in the previous year and 7.3 + 1.7 ng/ml in those with 0-1 crisis and no complications; independent sample t-test, p > 0.05, not significantly different.
Conclusion: Plasma concentration of fucosyltransferase7 is not associated with the number of vaso-occlusive events in sickle cell disease.
Funding: None declared.

Keywords: Fucosyltransferase7; adhesion molecules; sickle cell disease

DOI: https://doi.org/10.4314/gmj.v57i3.6

Science. 2024 Jul 05. 385(6704): 91-99

A molecular glue degrader of the WIZ transcription factor for fetal hemoglobin induction.

Sickle cell disease (SCD) is a prevalent, life-threatening condition attributable to a heritable mutation in β-hemoglobin. Therapeutic induction of fetal hemoglobin (HbF) can ameliorate disease complications and has been intently pursued. However, safe and effective small-molecule inducers of HbF remain elusive. We report the discovery of dWIZ-1 and dWIZ-2, molecular glue degraders of the WIZ transcription factor that robustly induce HbF in erythroblasts. Phenotypic screening of a cereblon (CRBN)-biased chemical library revealed WIZ as a previously unknown repressor of HbF. WIZ degradation is mediated by recruitment of WIZ(ZF7) to CRBN by dWIZ-1, as resolved by crystallography of the ternary complex. Pharmacological degradation of WIZ was well tolerated and induced HbF in humanized mice and cynomolgus monkeys. These findings establish WIZ degradation as a globally accessible therapeutic strategy for SCD.

DOI: https://doi.org/10.1126/science.adk6129

Am J Hematol. 2024 Jul 02.

Hydroxyurea to prevent brain injury in children with sickle cell disease (HU Prevent)-A randomized, placebo-controlled phase II feasibility/pilot study.

Central nervous system (CNS) injury is common in sickle cell disease (SCD) and occurs early in life. Hydroxyurea is safe and efficacious for treatment of SCD, but high-quality evidence from randomized trials to estimate its neuroprotective effect is scant. HU Prevent was a randomized (1:1), double-blind, phase II feasibility/pilot trial of dose-escalated hydroxyurea vs. placebo for the primary prevention of CNS injury in children with HbSS or HbS-β0-thalassemia subtypes of SCD age 12-48 months with normal neurological examination, MRI of the brain, and cerebral blood flow velocity. We hypothesized that hydroxyurea would reduce by 50% the incidence of CNS injury. Two outcomes were compared: primary-a composite of silent cerebral infarction, elevated cerebral blood flow velocity, transient ischemic attack, or stroke; secondary-a weighted score estimating the risk of suffering the consequences of stroke (the Stroke Consequences Risk Score-SCRS), based on the same outcome events. Six participants were randomized to each group. One participant in the hydroxyurea group had a primary outcome vs. four in the placebo group (incidence rate ratio [90% CI] 0.216 [0.009, 1.66], p = .2914) (~80% reduction in the hydroxyurea group). The mean SCRS score was 0.078 (SD 0.174) in the hydroxyurea group, 0.312 (SD 0.174) in the placebo group, p = .072, below the p-value of .10 often used to justify subsequent phase III investigations. Serious adverse events related to study procedures occurred in 3/41 MRIs performed, all related to sedation. These results suggest that hydroxyurea may have profound neuroprotective effect in children with SCD and support a definitive phase III study to encourage the early use of hydroxyurea in all infants with SCD.

DOI: https://doi.org/10.1002/ajh.27423

Bioorg Med Chem Lett. 2024 Jun 29. pii: S0960-894X(24)00267-1. [Epub ahead of print]110 129865

The search for pyruvate kinase-R activators; from a HTS screening hit via an impurity to the discovery of a lead series.

Chul Yu, Lina Quattrocchio Setti, Shahul Nilar, Zhe Li, Ming Yu, James Partridge, Rebeca Choy, Vincent Siu, Steven Strutt, Richard Zang, Peter Rademacher, Soheila Bahmanjah, Yekaterina Myslovaty, Manuel Zancanella.

Pyruvate kinase (PK) is an essential component of cellular metabolism, converting ADP and phosphoenolpyruvate (PEP) to pyruvate in the final step of glycolysis. Of the four unique isoforms of pyruvate kinase, R (PKR) is expressed exclusively in red blood cells and is a tetrameric enzyme that depends on fructose-1,6-bisphosphate (FBP) for activation. PKR deficiency leads to hemolysis of red blood cells resulting in anemia. Activation of PKR in both sickle cell disease and beta-thalassemia patients could lead to improved red blood cell fitness and survival. The discovery of a novel series of substituted urea PKR activators, via the serendipitous identification and diligent characterization of a minor impurity in an High Throughput Screening (HTS) hit will be discussed.

Keywords: High throughput screen; Non-malignant hematology; Pyruvate kinase; Urea

DOI: https://doi.org/10.1016/j.bmcl.2024.129865

Br J Haematol. 2024 Jun 30.

Mitochondrial regulation of erythropoiesis in homeostasis and disease.

Vijay Menon, Mary Slavinsky, Olivier Hermine, Saghi Ghaffari.

Erythroid cells undergo a highly complex maturation process, resulting in dynamic changes that generate red blood cells (RBCs) highly rich in haemoglobin. The end stages of the erythroid cell maturation process primarily include chromatin condensation and nuclear polarization, followed by nuclear expulsion called enucleation and clearance of mitochondria and other organelles to finally generate mature RBCs. While healthy RBCs are devoid of mitochondria, recent evidence suggests that mitochondria are actively implicated in the processes of erythroid cell maturation, erythroblast enucleation and RBC production. However, the extent of mitochondrial participation that occurs during these ultimate steps is not completely understood. This is specifically important since abnormal RBC retention of mitochondria or mitochondrial DNA contributes to the pathophysiology of sickle cell and other disorders. Here we review some of the key findings so far that elucidate the importance of this process in various aspects of erythroid maturation and RBC production under homeostasis and disease conditions.

Keywords: RBCs; erythropoiesis; mitochondria; mitochondrial biogenesis; mitochondrial metabolism; mitophagy; terminal erythroid maturation

DOI: https://doi.org/10.1111/bjh.19600