bims-conane Biomed News
on Congenital anemias
Issue of 2024–07–14
eleven papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo
  1. Hydroxyurea in sickle cell disease and invasive bacterial infections: a case-control study.
  2. Advances in pharmacotherapy for sickle cell disease: what is the current state of play?
  3. Current and emerging drug treatment strategies to tackle sickle cell anemia.
  4. The enigma of sickle cell hepatopathy: Pathophysiology, clinical manifestations and therapy.
  5. Red cell exchange modulates neutrophil degranulation responses in sickle cell disease.
  6. International Society for Cell & Gene Therapy Stem Cell Engineering Committee report on the current state of hematopoietic stem and progenitor cell-based genomic therapies and the challenges faced.
  7. Effect of Hb conformational changes on oxygen transport physiology.
  8. A Unique Case of a Compound Heterozygosity of Hemoglobin Korle-Bu and Sickle Cell Trait in a Military Trainee.
  9. Papillary necrosis, fluid intake, and sickle cell nephropathy: lessons for the clinical nephrologist.
  10. Gene therapy and gene editing strategies in inherited blood disorders.
  11. Preclinical safety assessment of modified gamma globin lentiviral vector-mediated autologous hematopoietic stem cell gene therapy for hemoglobinopathies.
  1. J Pediatric Infect Dis Soc. 2024 Jul 06. pii: piae071. [Epub ahead of print]
    Hydroxyurea in sickle cell disease and invasive bacterial infections: a case-control study.
    Alice Pascault, Bérengère Koehl, Valentine Brousse, Malika Benkerrou, Jean Gaschignard.
      Hydroxyurea decreases painful events among children with sickle cell disease but could increase the risk of infections in treated patients through leucopenia. We performed a case-control study, comparing hydroxyurea treatment for sickle cell disease in cases with an invasive bacterial infection and in controls without infection. No difference was found.
    Keywords:  early treatment; hydroxyurea; invasive bacterial infections; sickle cell disease; spleen function
    DOI:  https://doi.org/10.1093/jpids/piae071
  2. Expert Opin Pharmacother. 2024 Jul 08. 1-10
    Advances in pharmacotherapy for sickle cell disease: what is the current state of play?
    Sheinei Alan, Julie Kanter.
       INTRODUCTION: Despite over 100 years of neglect and insufficient funding, sickle cell disease has risen to the top of the discussions due to the recent approval of two new genetic therapies. Prior to these approvals, there were only four prior approved medications for sickle cell disease in spite of being the most common inherited blood disorder. The advent and expense of these new genetic therapies have finally brought the trials and tribulations associated with SCD including the suffering and early mortality of affected individuals to the much-needed limelight. Presently, questions about how these therapies will be used and what that means for ongoing pharmaceutical development remain.
    AREAS COVERED: Here, we wish to highlight the current medications and treatments for SCD using already published literature as well as scrutinize the tedious process of implementation for these newly approved commercial genetic therapies.
    EXPERT OPINION: In our expert opinion, despite the progress we have made, significant challenges remain and the most important requirement for any of these treatments is ensuring all affected individuals have access to a sickle cell specialist who can provide comprehensive care.
    Keywords:  Sickle cell; gene therapy; health disparity; hemoglobinopathy; targeted therapy
    DOI:  https://doi.org/10.1080/14656566.2024.2377711
  3. Expert Opin Emerg Drugs. 2024 Jul 11.
    Current and emerging drug treatment strategies to tackle sickle cell anemia.
    Yogindra Persaud, Alexis Leonard, Parul Rai.
       INTRODUCTION: Since its discovery in the early 1900s, sickle cell disease (SCD) has contributed significantly to the scientific understanding of hemoglobin and hemoglobinopathies. Despite this, now almost a century later, optimal medical management and even curative options remain limited. Encouragingly, in the last decade, there has been a push toward advancing the care for individuals with SCD and a diversifying interest in options to manage this disorder.
    AREAS COVERED: Here, we review the current state of disease modifying therapies for SCD including fetal hemoglobin inducers, monoclonal antibodies, anti-inflammatory modulators, and enzyme activators. We also discuss current curative strategies with specific interest in transformative gene therapies.
    EXPERT OPINION: SCD is a chronic, progressive disease that despite a century of clinical description, only now is seeing a growth and advance in therapeutic options to improve the lifespan and quality of life for individuals with SCD. We anticipate newly designed and even repurposed therapies that may work as a single agent or combination agents to tackle the progression of SCD. The vast majority of individuals living with SCD are unlikely to receive gene therapy, therefore improved disease management is critical even for those that may ultimately chose to pursue a potentially curative strategy.
    Keywords:  Bone marrow transplant; Gene therapy; HSCT; L-glutamine; Sickle cell; anemia; crizanlizumab; emerging therapies; hydroxyurea; voxelotor
    DOI:  https://doi.org/10.1080/14728214.2024.2379260
  4. Br J Haematol. 2024 Jul 08.
    The enigma of sickle cell hepatopathy: Pathophysiology, clinical manifestations and therapy.
    Insia Rizvi, Divya Solipuram, Navneet Kaur, Aqsa Komel, Saba Batool, Jennifer Wang.
      Sickle cell disease (SCD) is one of the most common genetic disorders in the world predominantly affecting economically disadvantaged populations. There is a notable discrepancy between the growing adult SCD population and available diagnostic and therapeutic interventions for SCD. Sickle cell hepatopathy (SCH) is an all-inclusive term to describe the acute and chronic liver manifestations of SCD. The pathophysiology of SCH follows no defined pattern or sequence that poses challenges to clinicians and researchers alike. Evidence is lacking for this underreported disease at various levels from diagnostic to therapeutic options. This paper reviews the basic pathophysiology, clinical features, biochemical and radiological findings of various SCH manifestations and outlines the management of each condition. Old and new therapy options in SCD including hydroxyurea, red blood cell exchange transfusion, ursodeoxycholic acid, voxelotor, l-glutamine and crizanlizumab have been reviewed to investigate the role of these options in treating SCH. The role of liver transplant, haematopoietic stem cell transplant and gene therapy in SCH patients have been reviewed.
    Keywords:  BMT; clinical haematology; gene therapy; liver disease; sickle cell anaemia; transfusion medicine
    DOI:  https://doi.org/10.1111/bjh.19620
  5. Transfusion. 2024 Jul 09.
    Red cell exchange modulates neutrophil degranulation responses in sickle cell disease.
    Grace M Lee, Kimberly Boyle, Milena Batchvarova, Martha Delahunty, Mark A Suggs, Gowthami M Arepally, Marilyn J Telen.
       BACKGROUND: Neutrophils in sickle cell disease (SCD) are activated, contributing to disease. Red cell exchange (RCE), with the goal of lowering hemoglobin S (HbS), is an important part of therapy for many SCD patients. Whether RCE impacts neutrophil reactivity is unknown.
    STUDY DESIGN AND METHODS: To determine the effect of RCE on neutrophil activation, SCD patients undergoing RCE in steady-state were enrolled. Neutrophil degranulation responses were examined before/after RCE. Kinetic studies were completed to determine the duration of the effect of RCE on neutrophil function. Degranulation results were examined in relation to white blood cell count, neutrophil count, and HbS levels. The effect of RCE on RBC phosphatidylserine (PS) exposure was examined as a possible contributor to modulation of neutrophil function by RCE.
    RESULTS: Twenty-two patients with SCD, genotype SS, who underwent RCE (average pre-RCE HbS 33 ± 14%) were included for the study. RCE significantly decreased neutrophil degranulation responses. The effect of RCE on neutrophil activation was unrelated to cell count and instead directly correlated with HbS. The effect of RCE on neutrophil activation was sustained over several days post-apheresis. Furthermore, while increased RBC PS exposure results in increased neutrophil degranulation, RCE decreases RBC PS exposure.
    DISCUSSION: To our knowledge, this is the first study demonstrating that RCE significantly decreases neutrophil activation in a sustained HbS-dependent manner. Modulation of PS exposure by RCE may be a contributing mechanism by which RCE modulates neutrophil activation. These studies raise the possibility that modulation of neutrophil activation contributes significantly to the therapeutic effect of RCE.
    Keywords:  apheresis; neutrophils; red cell exchange; sickle cell disease; transfusion
    DOI:  https://doi.org/10.1111/trf.17947
  6. Cytotherapy. 2024 Jun 06. pii: S1465-3249(24)00735-7. [Epub ahead of print]
    International Society for Cell & Gene Therapy Stem Cell Engineering Committee report on the current state of hematopoietic stem and progenitor cell-based genomic therapies and the challenges faced.
    Ashish O Gupta, Melissa Azul, Senthil Velan Bhoopalan, Allistair Abraham, Alice Bertaina, Alan Bidgoli, Carmem Bonfim, Amy DeZern, Jingjing Li, Chrystal U Louis, Duncan Purtill, Annalisa Ruggeri, Jaap Jan Boelens, Susan Prockop, Akshay Sharma.
      Genetic manipulation of hematopoietic stem cells (HSCs) is being developed as a therapeutic strategy for several inherited disorders. This field is rapidly evolving with several novel tools and techniques being employed to achieve desired genetic changes. While commercial products are now available for sickle cell disease, transfusion-dependent β-thalassemia, metachromatic leukodystrophy and adrenoleukodystrophy, several challenges remain in patient selection, HSC mobilization and collection, genetic manipulation of stem cells, conditioning, hematologic recovery and post-transplant complications, financial issues, equity of access and institutional and global preparedness. In this report, we explore the current state of development of these therapies and provide a comprehensive assessment of the challenges these therapies face as well as potential solutions.
    Keywords:  adrenoleukodystrophy; gene editing; gene therapy; hematopoietic stem cells; metachromatic leukodystrophy; sickle cell disease; thalassemia
    DOI:  https://doi.org/10.1016/j.jcyt.2024.06.002
  7. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2024 Mar 28. pii: 1672-7347(2024)03-0467-09. [Epub ahead of print]49(3): 467-475
    Effect of Hb conformational changes on oxygen transport physiology.
    Ziyue Yin, Doudou Li, Qianwen Guo, Rong Wang, Wenbin Li.
      Red blood cells (RBCs) are the primary mediators of oxygen transport in the human body, and their function is mainly achieved through conformational changes of hemoglobin (Hb). Hb is a tetramer composed of four subunits, with HbA being the predominant Hb in healthy adults, existing in two forms: tense state (T state) and relaxed state (R state). Endogenous regulators of Hb conformation include 2,3-diphosphoglyceric acid, carbon dioxide, protons, and chloride ions, while exogenous regulators include inositol hexaphosphate, inositol tripyrophosphate, benzabate, urea derivative L35, and vanillin, each with different mechanisms of action. The application of Hb conformational regulators provides new insights into the study of hypoxia oxygen supply issues and the treatment of sickle cell disease.
    Keywords:  anti-hypoxia; conformational regulators; hemoglobin; oxygen affinity
    DOI:  https://doi.org/10.11817/j.issn.1672-7347.2024.230199
  8. J Hematol. 2024 Jun;13(3): 116-120
    A Unique Case of a Compound Heterozygosity of Hemoglobin Korle-Bu and Sickle Cell Trait in a Military Trainee.
    Gartrell C Bowling, Niels A Ryden, Allen R Holmes, Lauren E Lee, Kristin Stoll.
      Hemoglobin Korle-Bu (Hb KB) is a rare and likely under-reported hemoglobin (Hb) variant resulting from an unusual point mutation on the beta-globin chain. Hb KB is typically clinically silent, and there are limited reports of Hb KB heterozygosity compounded with other hemoglobinopathies that can present with varying clinical phenotypes. Here, we report a case of compound Hb KB heterozygosity with Hb S in an asymptomatic military trainee with a positive sickle cell screening test. Hb capillary and gel electrophoresis predicted a compound Hb S/D-Punjab overlap, which foretells a severe clinical phenotype. Sequencing of the Hb beta gene HBB demonstrated Hb KB, allowing for a diagnosis that fit his asymptomatic clinical phenotype and allowed for retention in the military.
    Keywords:  Hemoglobin Korle-Bu; Hemoglobin subunit beta sequencing; Sickle cell trait
    DOI:  https://doi.org/10.14740/jh1257
  9. J Nephrol. 2024 Jul 11.
    Papillary necrosis, fluid intake, and sickle cell nephropathy: lessons for the clinical nephrologist.
    Domenico Cozzo, Silvio Pianca, Valentina Forni Ogna, Stefania D'Arpa, Pietro Ernesto Cippà, Antonio Bellasi.
      
    Keywords:  Alcohol consumption; Fluid intake; Renal papillary necrosis; Sickle cell nephropathy
    DOI:  https://doi.org/10.1007/s40620-024-01991-y
  10. J Genet Genomics. 2024 Jul 08. pii: S1673-8527(24)00180-2. [Epub ahead of print]
    Gene therapy and gene editing strategies in inherited blood disorders.
    Xuemei Song, JinLei Liu, Tangcong Chen, Tingfeng Zheng, Xiaolong Wang, Xiang Guo.
      Gene therapy has shown significant potential in treating various diseases, particularly inherited blood disorders such as hemophilia, sickle cell disease, and thalassemia. Advances in understanding the regulatory network of disease-associated genes have led to the identification of additional therapeutic targets for treatment, especially for β-hemoglobinopathies. Erythroid regulatory factor BCL11A offers the most promising therapeutic target for β-hemoglobinopathies and reduction of its expression using the commercialized gene therapy product Casgevy was approved for use in the UK and USA in 2023. Notably, the emergence of innovative gene editing technologies has further broadened the gene therapy landscape, presenting new possibilities for treatment. Intensive studies indicate that base editing and prime editing, built upon CRISPR technology, enable precise single-base modification in hematopoietic stem cells for addressing inherited blood disorders ex vivo and in vivo. In this review, we present an overview of the current landscape of gene therapies, focusing on clinical research and gene therapy products for inherited blood disorders, evaluation of potential gene targets, and the gene editing tools employed in current gene therapy practices, which provides an insight for the establishment of safer and more effective gene therapy methods for a wider range of diseases in the future.
    Keywords:  Gene editing; Gene therapy; Inherited blood disorders; Therapeutic targets; β-hemoglobinopathies
    DOI:  https://doi.org/10.1016/j.jgg.2024.07.004
  11. PLoS One. 2024 ;19(7): e0306719
    Preclinical safety assessment of modified gamma globin lentiviral vector-mediated autologous hematopoietic stem cell gene therapy for hemoglobinopathies.
    Mohammad Shadid, Archana Shrestha, Punam Malik.
      Previously, we reported the development of a human Aγ-globin gene lentivirus (LV), GbG, which expresses high levels of HbF to correct the sickle cell anemia (SCA) phenotype in the Berkeley SCA mouse model, and then modified the γ-globin gene by substituting glycine at codon 16 with aspartic acid in the Aγ-globin gene to generate GbGM LV. In the present study, we evaluated the long-term safety of human Aγ-globin gene carrying GbGM LV in wild-type mice after primary and secondary transplants of GbGM-modified hematopoietic stem cells (HSC) over 18 months. The safety of the GbGM bone marrow transplant was assessed by monitoring the effects on body weight, hematology, histopathology, malignancy formation, and survival. Mice transplanted with Mock-transduced and spleen focus forming virus (SFFV) γ-retroviral vector (RV)-transduced HSC served as negative and positive controls, respectively. The mean donor-cell engraftment was comparable across Mock, GbGM LV, and SFFV RV groups. There were no significant differences in body weight, clinical signs, immunophenotype, or histopathology in the GbGM-treated mice compared to controls. Four SFFV RV-treated mice, but none of the GbGM-treated mice, developed donor-derived, vector-positive lymphomas as demonstrated by flow cytometry analysis and in situ hybridization. These results highlight the safety of the administration of GbGM LV-modified HSC with long-term follow-up after primary and secondary transplants in mice. This data supported the initiation of phase 1/2 first-in-human SCA clinical trial in the United States.
    DOI:  https://doi.org/10.1371/journal.pone.0306719
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