RARE DISEASE
Sickle cell-beta-thalassemia disease syndrome
Sickle cell-beta-thalassemia disease syndrome
Sickle cell-beta-thalassemia disease syndrome
Synonyms: HbS-beta-thalassemia syndrome
Synonyms: HbS-beta-thalassemia syndrome
Synonyms: HbS-beta-thalassemia syndrome
Drug discovery
1
drug
With orphan designation
Overview
Sickle cell-beta-thalassemia disease syndrome is an inherited hemoglobinopathy caused by co-inheritance of sickle cell (HbS) and beta-thalassemia traits. Severity depends on beta-globin production: HbS β+ (milder anemia, residual normal hemoglobin) and HbS β⁰ (severe, akin to sickle cell anemia) [1][6][11]. Clinical features include chronic hemolytic anemia, vaso-occlusive crises, infection risk, and multi-organ complications [5][16]. Management requires lifelong hematologic surveillance, disease-modifying therapies, and prevention of end-organ damage [15][16].
Burden
Chronic morbidity: 67% of U.S. cases occur in high social vulnerability areas, exacerbating health inequities [2][4].
Mortality: SCD contributes to 376,000 annual deaths globally, with peak mortality in children <5 years [4][19].
Lifelong costs: Frequent hospitalizations, transfusions, and complications (e.g., stroke, pulmonary hypertension) [5][11][16].
Therapies
Hydroxyurea: Reduces crises and raises fetal hemoglobin (HbF) [16][19].
Transfusions/chelation: For severe anemia and stroke prevention [1][15].
Curative options: Allogeneic stem cell transplant (limited by donor availability) and gene therapy (e.g., exagamglogene autotemcel [Casgevy™], FDA-approved in 2023) [3][8][13].
Categories: rare genetic diseases, rare hematological diseases, rare transplant-related disorders
Research Papers
284 drug discovery papers about Sickle cell-beta-thalassemia disease syndrome, with 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
284 drug discovery papers about Sickle cell-beta-thalassemia disease syndrome, with 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2025-08-03 | Cutting the Gordian Knot of Iron, Oxygen Radicals, Erythropoiesis, and Red Cell Survival: Allosteric Regulation of Pyruvate Kinase Activity
Iron is an element critical to supporting a wide range of biological functions, chief among them being the support of oxygen transport and cellular respiration. However, iron reduction-oxidation reactions give rise to reactive oxygen species causing oxidative damage. Being both essential and potentially dangerous, iron metabolism from its absorption to utilization in erythropoiesis is tightly controlled. Erythrocyte health and oxygen delivery, reactive oxygen species generation and associated antioxidant activity are all interconnected through a network of feedback loops allowing for dynamic regulation in response to changing body requirements. When tangled by a pathology, this network becomes a real Gordian Knot. Resultant highly variable pathological homeostasis is reviewed with examples of pyruvate kinase (PK) deficiency, hereditary iron overload syndromes, chronic kidney disease, anemia of chronic inflammation, chronic Hepatitis C, beta-thalassemia and homozygous sickle cell disease, and blood transfusion therapy. Emerging understanding of the feedback links between different regulatory systems helps us to cut the metabolic Gordian Knot by tackling the underlying mechanisms of pathology, driving aberrant metabolism towards healthy homeostasis. One such opportunity lies in management of pathology-driven oxidative stress by modulation of the activity of the glycolytic cycle, specifically in the activation of its final energy producing step catalyzed by the pyruvate kinase enzyme. Allosteric regulation of its activity offers an attractive target in multiple therapeutic applications. Most of the evidence of clinical performance of pyruvate kinase activators comes from the work done with mitapivat (Agios Pharmaceuticals), a small-molecule allosteric PK activator that was granted an orphan drug designation by the Food and Drug Administration for PK deficiency, thalassemia, and sickle cell disease. It is currently approved for treatment of PK deficiency in adults and is under review for treatment of thalassemia. A number of other PK activity modulators are currently in development, with different PK isoforms targeted for a range of clinical applications. This potential is rooted in the ability of PK activators to re-activate the glycolytic pathway to generate energy for antioxidation systems, improve glucose utilization, and, in the case of the PK M2 isoform, shift the oligomeric balance away from the form associated with induced transcription of inflammatory cytokines. However, despite extensive research, application of PK activators in clinical practice remains limited. Available clinical evidence and emerging applications are discussed making a case for potential utility of PK activators in a wide spectrum of conditions associated with elevated reactive oxygen species production, increased oxidative stress and inflammation.
2024-05-31 | A Pharmacist-Managed Hydroxyurea Prescribing Protocol Improves Uptake and Optimization among Patients with Sickle Cell Disease
Sickle cell disease (SCD) is a common genetic disorder with potentially serious sequelae that can be effectively treated with hydroxyurea. Despite its favorable benefit-risk profile, hydroxyurea uptake in patients with SCD is low. A pilot study was conducted at the Southern Alberta Rare Blood and Bleeding Disorders (SARBBDs) Comprehensive Care Program between January 2020 and September 2023 to assess the implementation of a pharmacist-led protocol for supporting the uptake of hydroxyurea among eligible patients with SCD and optimizing its dosing. The protocol standardized the prescription, monitoring, dose titration, and patient counselling by a clinic pharmacist. The number of patients enrolled in the SARBBDs program increased from 98 in January 2020 to 168 in 2023. During this period, the proportion of patients on hydroxyurea increased from 37.8% to 62.5%, the proportion of patients on hydroxyurea who were at a maximum tolerated dose (MTD) increased from 35.1% to 63.8%, and the average hemoglobin F level increased from 13.9% to 19.7%. The mean time to reach MTD was 10 months and required eight pharmacist interventions, six laboratory assessments, and three dose increases. Hydroxyurea continuation rates were high, with most discontinuations resulting from loss to follow-up or transition to a transfusion management strategy. This real-world pilot study demonstrated that implementation of a pharmacist-led prescribing and monitoring protocol nearly doubled hydroxyurea uptake and achievement of MTD in patients with SCD managed in a rare blood disorders clinic.
2024-04-02 | Pharmacologic Therapies in Beta Hemoglobinopathies: Fetal Globin Gene Induction in the First Molecular Diseases
Beta hemoglobinopathies and thalassemias are caused by diverse molecular mutations of the βA globin chains and modulated by polymorphisms. These are important disorders in medical history, as they became prevalent globally in regions where P. falciparum malaria was endemic. Heterozygous or carrier states conferred a survival advantage; however, doubly heterozygous or homozygous states cause severe hemolytic anemia and multi-organ complications. These disorders are somewhat unique in that all humans have alternate genes for fetal globin chains, which are expressed in fetal life but are silenced on a developmental clock in infancy. An established approach to ameliorating conditions of abnormal adult globin genes is to reactivate, or increase expression, of the endogenous fetal globin genes to replace the missing protein chains in beta thalassemias or inhibit polymerization of hemoglobin S and reduce the red cell abnormalities. This review provides a high-level overview of cell and molecular mechanisms that mediate fetal to adult globin gene switching and pharmacologic therapies that can reactivate fetal globin through different actions. Intermittent or metronomic dosing regimens have overcome challenges of undesirable off-target effects by agents that cause erythroid cell growth arrest. Multiple pharmacologic candidates reactivate or increase the expression of fetal globin protein and proportions of red blood cells containing HbF (F-cells). Hydroxyurea maintains high levels of HbF if begun in infancy, with some decline in mid-childhood. It elicits lower responses in HbF in adult patients, but still has broad clinical benefit in reducing many complications. However, many adult patients do not tolerate optimal hydroxyurea dosing due to cytopenias. Parenterally administered therapies with differing molecular actions, such as demethylating agents and histone deacetylase inhibitors, have shown proof-of-principle in reactivating HbF. Orally bioavailable candidates with complementary molecular mechanisms are in trials. Combining fetal globin-inducing agents with other therapies with complementary mechanisms, such as recombinant erythropoietin that promotes the survival of red blood cells and therapeutics that promote erythroid cell metabolism, should have additive effects. These pharmaceutical candidates offer great clinical potential and global feasibility for ameliorating these serious diseases.
2024-04-01 | Pulmonary Hypertension in Sickle Cell Disease: Novel Findings of Gene Polymorphisms Related to Pathophysiology
Pulmonary hypertension (PH) is a progressive and potentially fatal complication of sickle cell disease (SCD) affecting 6-10% of adult SCD patients. Various mechanisms and theories have been evaluated to explain the pathophysiology of the disease. However, questions remain, particularly regarding the clinical heterogeneity of the disease in terms of symptoms, complications, and survival. Beyond the classical mechanisms that have been thoroughly investigated and include hemolysis, nitric oxide availability, endothelial disorders, thrombosis, and left heart failure, attention is focused nowadays on the potential role of the genes involved in such processes. Potential candidate genes are investigated through next-generation sequencing, with the TGF-β pathway being the initial target. This field of research may also provide novel targets for pharmacologic agents in the future as is already the case with idiopathic PH. The collection and processing of data and samples from multiple centers can yield safe results that will allow a better understanding of SCD-related PH as a part of the disease’s clinical spectrum. The following review attempts to capture the most recent findings of studies on gene polymorphisms that have been associated with PH in SCD patients.
2024-03-23 | Early Administration of Intravenous Hydration and Opioid Analgesics Is Correlated with Decreased Admission Rates during Vaso-Occlusive Episodes in Sickle Cell Disease
Background: Painful vaso-occlusive episodes (VOEs) are the hallmark of sickle cell disease (SCD) and account for frequent visits to the emergency department (ED) or urgent care (UC). Currently, the early administration of analgesics is recommended as initial management; however, there is a need for further understanding of the effect of prompt analgesics and hydration during VOEs. The objective of this study is to analyze the factors associated with the rate of hospital admission in the setting of time to intravenous (IV) analgesics and hydration. Method: This retrospective single-institution study reviewed adult and pediatric patients with SCD who presented with VOEs from January 2018 to August 2023. Results: Of 303 patient encounters, the rates of admission for the overall group, the subgroup which received IV hydration within 60 min of arrival, and the subgroup which received both IV analgesics and hydration within 60 min were 51.8%, 25.6% (RR = 0.46), and 18.2% (RR = 0.33), respectively. Further, factors such as gender and the use of hydroxyurea were found to be significantly associated with the rate of admission. Conclusions: This signifies the importance of standardizing the management of VOEs through the timely administration of IV analgesics and hydration in both adult and pediatric ED/UC.
cell therapies
2023-09-29 | Erythrocytapheresis in Children and Young Adults with Hemoglobinopathies and Iron Overload in Need of Iron Chelation Therapy
Limited data regarding erythrocytapheresis in children, adolescents, and young adults have been published. The aim of this study was to evaluate erythrocytapheresis, either as a standalone therapy or in combination with iron chelation therapy, in children and young adults with hemoglobinopathies in whom current iron chelation therapy is not sufficient in decreasing the iron overload during management. We retrospectively analysed erythrocytapheresis in 19 patients with hemoglobinopathies in need of iron chelation therapy diagnosed with sickle cell disease (SCD) or β-thalassemia major. Patients were divided into (1) a case cohort who received erythrocytapheresis alone or in combination with iron chelation therapy and (2) a control cohort who received oral iron chelation therapy alone. Serum ferritin and haemoglobin levels were compared at five different time points over a one-year period. In the erythrocytapheresis cohort, there was a significant decrease in serum ferritin (p < 0.001). In the iron chelation therapy alone cohort, there was no significant decrease in serum ferritin over time (p = 0.156). Comparing the evolution of median serum ferritin between therapy with erythrocytapheresis and iron chelation therapy showed a statistically significant difference (p = 0.008). Patients with β-thalassemia major receiving erythrocytapheresis showed a greater reduction in serum ferritin compared to patients without (p = 0.036). A difference could not be shown between the erythrocytapheresis and iron chelation single therapies (p = 0.100). This study showed an overall significant reduction in serum ferritin in patients with hemoglobinopathies treated with erythrocytapheresis in addition to iron chelation. A clinical, although not statistical, trend of higher haemoglobin levels was maintained. Erythrocytapheresis in paediatric patients with β-thalassemia major was as effective in decreasing ferritin levels as in previously reported studies with SCD. Erythrocytapheresis is a promising therapy for treating and preventing transfusion-related iron overload.
2023-02-09 | Recent updates of stem cell-based erythropoiesis
Blood transfusions are now an essential part of modern medicine. Transfusable red blood cells (RBCs) are employed in various therapeutic strategies; however, the processes of blood donation, collection, and administration still involve many limitations. Notably, a lack of donors, the risk of transfusion-transmitted disease, and recent pandemics such as COVID-19 have prompted us to search for alternative therapeutics to replace this resource. Originally, RBC production was attempted via the ex vivo differentiation of stem cells. However, a more approachable and effective cell source is now required for broader applications. As a viable alternative, pluripotent stem cells have been actively used in recent research. In this review, we discuss the basic concepts related to erythropoiesis, as well as early research using hematopoietic stem cells ex vivo, and discuss the current trend of in vitro erythropoiesis using human-induced pluripotent stem cells.
2021-05-28 | Prospects for Stem Cell-Based Regenerative Therapies in India
Stem cells offer a promising therapeutic strategy to not only treat several incurable diseases but also regenerate damaged tissues. The current global boom in the field of stem cell and regenerative therapies had led to India becoming a global hotspot for stem cell-based therapies. In this review, we assess the current status of stem cell therapy trials in India and show that the bone marrow-derived stem cells, like mesenchymal stem/stromal cells (MSCs), are predominantly used. Phase 1 and 2 clinical trials have also used MSCs to alleviate symptoms of severe novel coronavirus infections. Recent breakthroughs in gene editing technologies, combined with stem cell therapy, can be effectively harnessed to devise large-scale and affordable treatments for haematological diseases that are highly prevalent in India, like beta-thalassemia and sickle cell diseases. Innovations in stem cell therapy in India can make treatments more affordable to address the needs of in-country patients.
2020-02-17 | Stem cells in the treatment of sickle cell disease
Sickle Cell Disease (SCD) is autosomal recessive disorder that is the result of a point mutation in the coding region of the beta globin gene. Polymerization of red blood cells with the sickle hemoglobin result in painful clinical symptoms and early death due to end organ failure. Improvement of treatment has extended the survival of adolescents into adulthood and offers relief of symptoms but does not offer a cure against the diagnosis being the inevitable cause of an early death. In addition, response to therapies vary between patients depending on their responsiveness and metabolism of medications. Hematopoietic stem cell transplantation offers reduction of recipient Hb S through replacing it with Hb A from the donor. Increased use of hematopoietic stem cell transplantation (HSCT) offers a curative therapy for patients with SCD that have access to an HLA-identical donor. However, limitations to indications for HSCT result due to associated toxicities with myeloablative conditioning and risk of graft failure. Reduced intensity and non-myeloablative conditioning look at reducing associated toxicities and making HSCT readily available for the adult population through mixed chimerism. In addition, clinical trials looking at alternative donors and gene therapies expand the availability of HSCT for the vast majority of patients without an HLA-identical donor.
2019-11-15 | Choice of Donor Source and Conditioning Regimen for Hematopoietic Stem Cell Transplantation in Sickle Cell Disease
In the United States, one out of every 500 African American children have sickle cell disease (SCD), and SCD affects approximately 100,000 Americans. Significant advances in the treatment of this monogenetic disorder have failed to substantially extend the life expectancy of adults with SCD over the past two decades. Hematopoietic stem cell transplantation (HSCT) remains the only curative option for patients with SCD. While human leukocyte antigen (HLA) matched sibling HSCT has been successful, its availability is extremely limited. This review summarizes various conditioning regimens that are currently available. We explore recent efforts to expand the availability of allogeneic HSCT, including matched unrelated, umbilical cord blood, and haploidentical stem cell sources. We consider the use of nonmyeloablative conditioning and haploidentical donor sources as emerging strategies to expand transplant availability, particularly for SCD patients with complications and comorbidities who can undergo neither matched related transplant nor myeloablative conditioning. Finally, we show that improved conditioning agents have improved success rates not only in the HLA-matched sibling setting but also alternative donor settings.
gene therapies
2024-06-10 | CRISPR RNA-Guided Gene Editing and its Clinical Research Applications in Hematology with Focus on Inherited Germline Predisposition to Hematologic Malignancies
Clustered regularly interspaced short palindromic repeats (CRISPR) based gene-editing has begun to transform the treatment landscape of genetic diseases. The history of the discovery of CRISPR/CRISPR-associated (Cas) proteins/single guide RNA (sgRNA)-based gene-editing since the first report of repetitive sequences of unknown significance in 1987 is fascinating, instructive, and inspiring for future advances. The recent approval of CRISPR-Cas9-based gene therapy to treat patients with severe sickle cell anemia and transfusion-dependent beta thalassemia has renewed hope for treating other hematologic diseases, including patients with germline predisposition to hematologic malignancies, who would benefit greatly from the development of CRISPR-based gene therapies. The purpose of this manuscript is three-fold: first, a chronological description of the history of CRISPR-Cas9-sgRNA-based gene editing; second, a brief description of the current state of clinical research in hematologic diseases, including selected applications in treating hematologic diseases with CRISPR-based gene therapy; and third, the current progress in gene therapies in inherited hematologic diseases and bone marrow failure syndromes, to hopefully stimulate efforts towards developing these therapies for patients with inherited bone marrow failure syndromes and other inherited conditions with germline predisposition to hematologic malignancies.
2024-04-18 | Applications of gene modification technologies in the treatment of inherited diseases
Introduction and Purpose: In last years gene modification technologies such as CRISPR/Cas9 has had a revolutionary impact on the treatment of inherited diseases. Technologies developed from bacterial defense mechanisms, has become a basic tools in scientific research and medical therapies. In our article we provided an overview of applications of gene modifications technologies, directly focusing on CRISPR/Cas9, in genetic disease treatment.
State of Knowledge: New applications of CRISPR/Cas9 are still being explored. Treating inherited diseases such as cystic fibrosis, Duchenne muscular dystrophy, thalassemia, hemophilia, Huntington's disease, Crigler-Najjar syndrome, sickle cell anemia, Marfan syndrome, and phenylketonuria, is feasible with this novel technique. A comparative analysis with other gene editing methods highlights CRISPR/Cas9's efficacy, ease of use, and multiplexing capabilities.
Summary: CRISPR/Cas9 is a groundbreaking technology with broad applications in genetic research and therapy. Its ease of use, cost-effectiveness, and ability to target multiple genes simultaneously position it as a preferred method. However, there are some challenges associated with precision issues and ethical considerations in human embryo gene editing. As CRISPR/Cas9 continues to evolve, responsible application and ethical considerations are important for maximizing its potential in treatment of genetic diseases.
2024-04-06 | Impact of hospitalized vaso-occlusive crises in the previous calendar year on mortality and complications in adults with sickle cell disease: a French population-based study
BackgroundHistorically, sickle cell disease (SCD) patients experiencing frequent hospitalized vaso-occlusive crises (HVOC) have been associated with increased mortality, yet recent data reflecting the widespread use of hydroxyurea and advancements in disease management remain limited. Our study aims to assess the association between HVOC and mortality or severe complications in patients with SCD in this new treatment landscape.MethodsThis was a retrospective observational cohort study using the French national health data system. Between 01-01-2012 and 12-31-2018, all SCD patients ≥16 years old (ICD-10 codes D57.0–2) were included and followed until 12-31-2018. HVOC was defined as a hospitalization of ≥1 night with primary diagnosis of SCD with crisis, following an emergency room visit. The association between HVOC and severe complications was assessed with a Cox proportional hazards model.FindingsIn total, 8018 patients (56.6% females; 4538/8018) were included. The 2018 SCD standardized one-year period prevalence was 17.9 cases/100,000 person-years [17.4; 18.3]. The mean rate was 0.84 (1.88) HVOC/person-year. In 2018, 70% (5323/7605), 22% (1671/7605), and 8% (611/7605) of patients experienced 0, 1–2, or 3+ HVOCs, respectively. The median survival time between HVOCs was 415 days [386; 439]. Overall, 312 patients died (3.9%) with a mean age of 49.8 (19.4). Compared to patients without HVOC, the hazard ratios of death in patients with 1–2 or 3+ HVOCs the year prior to death were 1.67 [1.21; 2.30] and 3.70 [2.30; 5.93], respectively. Incidence of acute chest syndrome, pulmonary embolism, osteonecrosis, and sepsis increased with the HVOCs category, but not stroke. In 2018, 29.5% (180/611) of patients with 3+ HVOCs did not take hydroxyurea.InterpretationPatients must be closely monitored during their hospitalizations to intensify treatment and check treatment compliance. Innovative therapies are also required.FundingThe study was funded by Novartis.
2024-02-15 | The Italian breakthrough in CRISPR trials for rare diseases: a focus on beta-thalassemia and sickle cell disease treatment
The development of gene therapy and the current advantageous method of clustered regularly interspaced short palindromic repeats (CRISPRs) has allowed the implementation of several clinical trials aimed at studying the possible efficacy of gene therapy for rare diseases. Rare diseases pose a global challenge, in that their collective impact on health systems is considerable, whereas their individually rare occurrence hinders research and development of efficient therapies. Despite the low prevalence of individual rare diseases, there are more than 7,000 defined rare diseases affecting 3.5–5.9% of the global population. Rare diseases are mostly chronic and approximately 80% are caused by genetic mutation with an early-life onset. In Italy, in 2021 were recorded more than 400,000 people with rare disease. Because of its location and history, Italy has an unfortunate statistic regarding the presence and prevalence of two rare genetic diseases, namely beta-thalassemia, of which there are about 90 million carriers worldwide, 400,000 of whom are actually affected, and sickle cell disease, with about 300 million carriers and 6.5 million people affected worldwide. Advancements in genomic studies allowed Italy to join clinical trials to study effective and resolving gene therapies for BT and SCD. This study reports on the impact of rare diseases in Italy, ongoing studies, and recent achievements in BT and SCD trials using the CRISPR method and remaining hurdles in the application of CRISPR technology to rare diseases, also taking a glimpse at the newest challenges and future opportunities in the genetic treatment for rare diseases.
2023-09-20 | Global Trends on β-thalassemia Research over 10 Years: A Bibliometric Analysis
Abstract Introduction Thalassemia, an inherited quantitative globin disorder, is the most prevalent monogenic disease globally. While severe alpha thalassemia results in intrauterine death, β-thalassemia manifests during childhood due to the "second conversion of hemoglobin," garnering increased attention in recent decades. Methods In this study, a bibliometric analysis will be conducted of thalassemia articles published in the Web of Science Core Collection database between 2013 and 2023 to establish a comprehensive overview and to identify emerging trends. A total of 5655 studies published between 2013 and 2023 were systematically retrieved, and annual publications demonstrated a steady increase, maintaining a high level over the past decade. Results The United States contributed the highest number of publications, followed by China. Notably, the journal Blood emerged as the leading authority in β-thalassemia research. Analysis of research hotspots revealed that the pathogenesis of β-thalassemia is primarily linked to iron overload, anemia, gene mutations, and ineffective erythropoiesis. Furthermore, recent studies focusing on gene editing therapies present promising avenues for future investigation. Conclusion These findings grasp the research status of β-thalassemia and shed new light on future research frontiers.
antibodies
2023-04-01 | 5588995 COMPARATIVE EFFICACY AND SAFETY OF PHARMACOLOGICAL INTERVENTIONS FOR SICKLE CELL DISEASE IN CHILDREN AND ADOLESCENTS: A NETWORK META-ANALYSIS
Background: Sickle cell disease (SCD), an inherited hemoglobinopathy characterized by anemia, severe pain, acute chest syndrome (ACS) and vaso-occlusive crisis (VOC), has important impact on morbidity and mortality worldwide, especially in the pediatric population (over 50% die before age of 5). Although few treatment options are available, new disease modifying therapies, intended to prevent or reduce SCD-related complications are under development. Previous systematic reviews are limited to adult patients or focused only on gathering data of few therapies. Aims: Our aim was to synthetize the evidence on the efficacy and safety profiles of pharmacological interventions for managing SCD in children and adolescents. Methods: A systematic review with searches in PubMed, Scopus, and Web of Science was performed (May-2022). The protocol is registered at PROSPERO CRD42022328471. We included randomized controlled trials comparing any disease-modifying agent used to treat SCD complications in patients under 18 years old. The outcomes of interest included: VOC, ACS, transfusions, hospital admission, discontinuation, serious adverse events. Data were pooled by means of Bayesian network meta-analyses with surface under the cumulative ranking curve analyses (SUCRA). Results were reported as odds ratio (OR) with 95% credibility intervals (CrI). Additionally, stochastic multicriteria acceptability analyses (SMAA) were performed. The methodological quality of the trials and certainty of evidence were evaluated through RoB 2.0 tool and GRADE approach, respectively. Results: Overall, 17 randomized controlled trials (n=1,972 patients) published between 1982-2022, conducted mostly in Africa (41%) and North America (35%) were included for analyses. Around one-third of the trials were restricted to homozygous patients for the SCD allele (SS HMZ); yet when reported, patients with heterozygous S-C combination represented less than 30% of the population. Males accounted for 49.0% of the cases, with ages varying from 1-19 years old. Almost all trials (n=15, 88.2%) directly compared active drugs with placebo. The evaluated interventions were: hydroxyurea [n=6 trials], L-arginine [n=3], antiplatelets [n=2], immunotherapy/monoclonal antibodies [n=2], sulphates [n=2], docosahexaenoic acid [n=1], niprisan [n=1] (Figure 1). SUCRA and SMAA revealed that immunotherapy/monoclonal antibodies and hydroxyurea 20 mg/kg are potentially more effective against ACS (17% and 24% probabilities, respectively), VOC (around 29% and 20%, respectively) and needing of transfusions (around 25%), while L-arginine (100-200 mg/kg) and placebo were more associated with these events. Although therapies were overall considered safe, antiplatelet and sulfates may lead to more discontinuations and severe adverse events (uncertainty evidence). Results were similar between age subgroups (<10 years vs. 10-19 years). Summary - Conclusion: The available evidence on the effect of drugs for managing SCD in children and adolescents is still insufficient and weak. No clear definition and reporting criteria for some outcomes exist. Hydroxyurea 20 mg/kg/day may remain the standard of care for these patients, however, long-term, well-designed trials comparing new immunotherapy/monoclonal antibodies should be performed. The use of monotherapies with L-arginine, antiplatelets or sulphates should be avoided given the poor benefit-risk ratio for this population.References 1. Brandow et al, J Hematol Oncol 2022; 15(1):20 2. Quinn et al, Pediatr Blood Cancer 2022; 69(8):e29805 3. Tonin et al, Pharm Pract (Granada) 2017; 15(1):943
2023-01-25 | A cross-sectional study on pain management during vaso-occlusive crisis in sickle cell disease
Background: Sickle cell disease is an inherited hematological disorder characterized by hard and sticky red blood cells that appears like a C-shaped “sickle” in contrast to the healthy, round red blood cells which tend to stick and clog the blood vessels during blood flow leading to pain or vaso-occlusive crisis. Methods: A cross-sectional study was conducted at Yashoda hospital in Hyderabad, India. Data regarding the management of acute pain during VOC in SCD patients was gathered from the hematology department on a daily basis during the duration of the study. The data was recorded in an online questionnaire form and a subsequent DUE was conducted. Results: Among all the patients that were enrolled in the study, acute pain as VOC was presented in 72%, whereas 28% did not experience pain. Pain was manifested as acute chest syndrome, generalized body pain, headache. Crizanlizumab, a monoclonal antibody was administered to patients who were ≥16 years to decrease the frequency of VOC. Upon DUE, per prescription distribution of crizanlizumab was 11.2%, while 88.8% constituted of anti-metabolites, antibiotics, analgesics, opiate antagonist, etc. Frequency of use of crizanlizumab among SCD patients was 69.23% Conclusions: Management of VOC cannot be described as one size fits all. Interindividual variability must be considered at all times during planning and implementing a treatment regimen. Assessment of pain on pain scale to ensure targeted treatment at maximum effective concentration followed by titration of dose to reduce the occurrence of tolerance, withdrawal, dependence and addiction should be basis of management.
2017-08-23 | Pathways to pulmonary hypertension in sickle cell disease: the search for prevention and early intervention
Pulmonary hypertension (PH) develops in a significant number of patients with sickle cell disease (SCD), resulting in increased morbidity and mortality. This review focuses on PH pathophysiology, risk stratification, and new recommendations for screening and treatment for patients with SCD. Areas covered: An extensive PubMed literature search was performed. While the pathophysiology of PH in SCD is yet to be fully deciphered, it is known that the etiology is multifactorial; hemolysis, hypercoagulability, hypoxemia, ischemic-reperfusion injury, oxidative stress, and genetic susceptibility all contribute in varying degrees to endothelial dysfunction. Hemolysis, in particular, seems to play a key role by inciting an imbalance in the regulatory axis of nitric oxide and arginine metabolism. Systematic risk stratification starting in childhood based on clinical features and biomarkers that enable early detection is necessary. Multi-faceted, targeted interventions, before irreversible vasculopathy develops, will allow for improved patient outcomes and life expectancy. Expert commentary: Despite progress in our understanding of PH in SCD, clinically proven therapies remain elusive and additional controlled clinical trials are needed. Prevention of disease starts in childhood, a critical window for intervention. Given the complex and multifactorial nature of SCD, patients will ultimately benefit from combination therapies that simultaneously targets multiple mechanisms.
2017-03-08 | Evaluation of anti-inflammatory response in sickle cell anemia patients
Background and objective: Inflammation has been implicated in the pathogenesis of most complications seen in Sickle cell anemia (SCA) patients.This project aimed to evaluate serum levels of two newly discovered anti-inflammatory cytokines IL-27 and IL-37 and some pro-inflammatory cytokines among Brazilian SCA patients that are hydroxurea-naive and compared with hydroxyurea-treated patients and HbAA controls.Furthermore, to demonstrate the effect of IL-27, IL-37 and heme on in vitro secretion of IL-8 in human neutrophils and monocytes.Methods: It is a cross-sectional study of 82 consenting SCA (35 hydroxyureanaïve HbSS and 47 hydroxyurea-treated HbSS) patients in steady state and 49 HbAA consenting individuals.Their clinical details were obtained by interview and from patients' records.The serum levels of IL-27, IL-37, TGF-β, TNF-α, IL-1β, IL-6 and IL-8 were quantified by ELISA.Neutrophils and monocytes were isolated from healthy controls, cultured separately without or with cytokines (IL-27 and IL-37) and heme.The pro-inflammatory cytokines in the supernatant were detected by ELISA, Results: Serum levels of IL-27, IL-37, IL-1β, IL-6 and IL-8 in hydroxyurea-naïve SCA patients were significantly elevated compared to HbAA controls There was no significant difference in the serum levels of both anti-and pro-inflammatory cytokines except IL-8 in the HU-treated SCA patients compared to controls.IL-27 and IL-37 were positively correlated in both HU-naive and hydroxyurea-treated HbSS patients.In vitro IL-8 production by IL-27 and IL-37 pre-treated neutrophils and monocytes was significantly inhibited despite addition of heme.Conclusions: Our findings show that IL-27 and IL-37 are elevated in HU-naïve patients.The study support that the use of HU did not significantly alter serum levels of anti-and pro-inflammatory cytokines except IL-8 in SCA patients.IL-27 and IL-37 may play a regulatory role on the pro-inflammatory pathways, as suggested by the in vitro studies.This role is probably sufficient to prevent further cellular or tissue damage but not potent enough to prevent inflammation.Thus, IL-27 and IL-37 may be potential immuno-targets to ameliorate complications associated with elevated heme as seen in SCA and other hemolytic anemias.
2016-10-21 | BILATERAL CHOROIDAL NEOVASCULARIZATION IN A PATIENT WITH BETA-THALASSEMIA MAJOR AND ITS MANAGEMENT
Purpose: To describe a case of bilateral choroidal neovascularization in a patient with beta-thalassemia major and an interventional therapeutic attempt. Method: Retrospective case report. Result: A known case of beta-thalassemia major presented with gradual vision loss. Fundoscopy revealed bilateral macular edema accompanied by intraretinal hemorrhages. Optical coherence tomography and fluorescein angiography were compatible with the diagnosis of choroidal neovascularization. No signs of angioid streaks or other related abnormalities were noticed in examination and imaging. The patient was treated with intravitreal bevacizumab, and visual acuity improved within 6 months of follow-up. Conclusion: Bilateral choroidal neovascularization can be a presenting pathology in patients with beta-thalassemia major. Anti–vascular endothelial growth factor is a promising treatment option.
other
2024-02-08 | Beta-Thalassemia: A Pharmacological Drug-Based Treatment
This review was performed to determine the potential of drugs that can remove or decrease the requirements for blood transfusion among beta (β)-thalassemia patients. A comprehensive literature search was conducted to identify clinical trials and studies using PubMed Central, Google Scholar, PubMed, and ScienceDirect archived articles published from 1996 to November 2023. According to this review, clinical trials for a number of drugs, including luspatercept, sotatercept, mitapivat, etavopivat, hydroxyurea, rapamycin, decitabine, thalidomide, and quercetin, have been performed as part of efforts to improve the cure strategy for β-thalassemia. Of these drugs, luspatercept and sotatercept have exhibited particularly promising results and have been granted US Food and Drug Administration (FDA) approval for use in β-thalassemia patients. The mode of action for the drugs luspatercept and sotatercept involves the stimulation of hemoglobin (Hb) production or enhancement of its functionality, thereby decreasing reliance on blood transfusions and enhancing the overall quality of life. In this way, drugs like luspatercept and sotatercept present an opportunity to notably decrease the necessity for blood transfusions in β-thalassemia patients, improving their standard of living and overall prognosis. However, more research is needed to evaluate the effectiveness and safety of these drugs in the long run.
2022-05-12 | Targeting Genetic Modifiers of HBG Gene Expression in Sickle Cell Disease: The miRNA Option
Sickle cell disease (SCD) is one of the most common inherited hemoglobinopathy disorders that affects millions of people worldwide. Reactivation of HBG (HBG1, HBG2) gene expression and induction of fetal hemoglobin (HbF) is an important therapeutic strategy for ameliorating the clinical symptoms and severity of SCD. Hydroxyurea is the only US FDA-approved drug with proven efficacy to induce HbF in SCD patients, yet serious complications have been associated with its use. Over the last three decades, numerous additional pharmacological agents that reactivate HBG transcription in vitro have been investigated, but few have proceeded to FDA approval, with the exception of arginine butyrate and decitabine; however, neither drug met the requirements for routine clinical use due to difficulties with oral delivery and inability to achieve therapeutic levels. Thus, novel approaches that produce sufficient efficacy, specificity, and sustainable HbF induction with low adverse effects are desirable. More recently, microRNAs (miRNAs) have gained attention for their diagnostic and therapeutic potential to treat various diseases ranging from cancer to Alzheimer’s disease via targeting oncogenes and their gene products. Thus, it is plausible that miRNAs that target HBG regulatory genes may be useful for inducing HbF as a treatment for SCD. Our laboratory and others have documented the association of miRNAs with HBG activation or suppression via silencing transcriptional repressors and activators, respectively, of HBG expression. Herein, we review progress made in understanding molecular mechanisms of miRNA-mediated HBG regulation and discuss the extent to which molecular targets of HBG might be suitable prospects for development of SCD clinical therapy. Lastly, we discuss challenges with the application of miRNA delivery in vivo and provide potential strategies for overcoming barriers in the future.
2019-05-17 | Potential Therapeutic Modalities of Reawakening Fetal Hemoglobin Simulated by Reaction Systems
Thalassemia syndromes are a diverse group of inherited genetic disorders.There are different types of thalassemia disorders, such as, β-thalassemia, which is also called Mediterranean anemia, that is an inherited disease that played a major role in the American thriller movie, "Dying of the light" starring Nicolas Cage (Dec.2014).In this study, we focus on the beta-globin (β-globin) gene family related disorders.We seek potential amelioration strategies for β-thalassemia and sickle cell anemia via γ-globin gene induction.In this work, a simulation model is developed, utilizing a reaction systems methodology.These systems are finite and based on a discrete time scale and can be used to describe and analyze complex biological systems and biological phenomenon.In our model, simulations of normal and abnormal cases of fetal, to adult hemoglobin switching developmental stage are illustrated.Various types of known and potential treatment strategies for β-thalassemia and sickle cell anemia cases from the literature have been utilized to validate our model, used for identifying new potential treatments to be tested by molecular biologists, in the future studies.Moreover, we propose a novel potential simulation, as a therapeutic means, for β-thalassemia and sickle cell anemia, by identifying FOG1 as a potential target.Finally, our proposed model, based on a reaction systems methodology, shows that inhibition of FOG1 expression by using methods, such as, RNAi induces γ-globin gene expression and can compensate for the lack of beta-globin in patients suffering from β-globin gene related diseases, such as, β-thalassemia and sickle cell anemia.
2013-02-21 | Hemolysis and free hemoglobin revisited: exploring hemoglobin and hemin scavengers as a novel class of therapeutic proteins
Abstract Hemolysis occurs in many hematologic and nonhematologic diseases. Extracellular hemoglobin (Hb) has been found to trigger specific pathophysiologies that are associated with adverse clinical outcomes in patients with hemolysis, such as acute and chronic vascular disease, inflammation, thrombosis, and renal impairment. Among the molecular characteristics of extracellular Hb, translocation of the molecule into the extravascular space, oxidative and nitric oxide reactions, hemin release, and molecular signaling effects of hemin appear to be the most critical. Limited clinical experience with a plasma-derived haptoglobin (Hp) product in Japan and more recent preclinical animal studies suggest that the natural Hb and the hemin-scavenger proteins Hp and hemopexin have a strong potential to neutralize the adverse physiologic effects of Hb and hemin. This includes conditions that are as diverse as RBC transfusion, sickle cell disease, sepsis, and extracorporeal circulation. This perspective reviews the principal mechanisms of Hb and hemin toxicity in different disease states, updates how the natural scavengers efficiently control these toxic moieties, and explores critical issues in the development of human plasma–derived Hp and hemopexin as therapeutics for patients with excessive intravascular hemolysis.
2006-12-21 | Silencing and reactivation of gamma-globin expression in humans
A new erythroblastic leukemia cell line (EEB) was established from a patient with early erythroblastic leukemia. The cells had features of immature erythroblasts, including an agranular basophilic cytoplasm and CD36, CD71, CD175s (sialyl-Tn) and CD235a (glycophorin A) expression without CD41 expression, myeloperoxidase activity and platelet-peroxidase activity. The cells were confirmed to be of the erythroid lineage based on expression of the gamma-globin message. They were induced to differentiate into benzidine-positive cells by hemin and δ-amino levulinic acid (δ-ALA). An analysis of cell membrane lipids showed that EEB cells contain a type of glycerolipid, phosphatidylglucose (PhGlc), but not unbranched type 2 chains, i antigens. GL-7 which is a recombinant Fab fragment of GL-2 and binds to PhGlc, induced production of hemoglobin F (HbF) associated with accumulation of the gamma-globin (γ-globin) message in EEB cells. The GL-7-mediated erythroid differentiation was associated with apoptosis. These results suggest that direct signaling to PhGlc mediates erythroid differentiation and apoptosis in EEB cells.
small molecules
2025-08-03 | Cutting the Gordian Knot of Iron, Oxygen Radicals, Erythropoiesis, and Red Cell Survival: Allosteric Regulation of Pyruvate Kinase Activity
Iron is an element critical to supporting a wide range of biological functions, chief among them being the support of oxygen transport and cellular respiration. However, iron reduction-oxidation reactions give rise to reactive oxygen species causing oxidative damage. Being both essential and potentially dangerous, iron metabolism from its absorption to utilization in erythropoiesis is tightly controlled. Erythrocyte health and oxygen delivery, reactive oxygen species generation and associated antioxidant activity are all interconnected through a network of feedback loops allowing for dynamic regulation in response to changing body requirements. When tangled by a pathology, this network becomes a real Gordian Knot. Resultant highly variable pathological homeostasis is reviewed with examples of pyruvate kinase (PK) deficiency, hereditary iron overload syndromes, chronic kidney disease, anemia of chronic inflammation, chronic Hepatitis C, beta-thalassemia and homozygous sickle cell disease, and blood transfusion therapy. Emerging understanding of the feedback links between different regulatory systems helps us to cut the metabolic Gordian Knot by tackling the underlying mechanisms of pathology, driving aberrant metabolism towards healthy homeostasis. One such opportunity lies in management of pathology-driven oxidative stress by modulation of the activity of the glycolytic cycle, specifically in the activation of its final energy producing step catalyzed by the pyruvate kinase enzyme. Allosteric regulation of its activity offers an attractive target in multiple therapeutic applications. Most of the evidence of clinical performance of pyruvate kinase activators comes from the work done with mitapivat (Agios Pharmaceuticals), a small-molecule allosteric PK activator that was granted an orphan drug designation by the Food and Drug Administration for PK deficiency, thalassemia, and sickle cell disease. It is currently approved for treatment of PK deficiency in adults and is under review for treatment of thalassemia. A number of other PK activity modulators are currently in development, with different PK isoforms targeted for a range of clinical applications. This potential is rooted in the ability of PK activators to re-activate the glycolytic pathway to generate energy for antioxidation systems, improve glucose utilization, and, in the case of the PK M2 isoform, shift the oligomeric balance away from the form associated with induced transcription of inflammatory cytokines. However, despite extensive research, application of PK activators in clinical practice remains limited. Available clinical evidence and emerging applications are discussed making a case for potential utility of PK activators in a wide spectrum of conditions associated with elevated reactive oxygen species production, increased oxidative stress and inflammation.
2024-05-31 | A Pharmacist-Managed Hydroxyurea Prescribing Protocol Improves Uptake and Optimization among Patients with Sickle Cell Disease
Sickle cell disease (SCD) is a common genetic disorder with potentially serious sequelae that can be effectively treated with hydroxyurea. Despite its favorable benefit-risk profile, hydroxyurea uptake in patients with SCD is low. A pilot study was conducted at the Southern Alberta Rare Blood and Bleeding Disorders (SARBBDs) Comprehensive Care Program between January 2020 and September 2023 to assess the implementation of a pharmacist-led protocol for supporting the uptake of hydroxyurea among eligible patients with SCD and optimizing its dosing. The protocol standardized the prescription, monitoring, dose titration, and patient counselling by a clinic pharmacist. The number of patients enrolled in the SARBBDs program increased from 98 in January 2020 to 168 in 2023. During this period, the proportion of patients on hydroxyurea increased from 37.8% to 62.5%, the proportion of patients on hydroxyurea who were at a maximum tolerated dose (MTD) increased from 35.1% to 63.8%, and the average hemoglobin F level increased from 13.9% to 19.7%. The mean time to reach MTD was 10 months and required eight pharmacist interventions, six laboratory assessments, and three dose increases. Hydroxyurea continuation rates were high, with most discontinuations resulting from loss to follow-up or transition to a transfusion management strategy. This real-world pilot study demonstrated that implementation of a pharmacist-led prescribing and monitoring protocol nearly doubled hydroxyurea uptake and achievement of MTD in patients with SCD managed in a rare blood disorders clinic.
2024-04-02 | Pharmacologic Therapies in Beta Hemoglobinopathies: Fetal Globin Gene Induction in the First Molecular Diseases
Beta hemoglobinopathies and thalassemias are caused by diverse molecular mutations of the βA globin chains and modulated by polymorphisms. These are important disorders in medical history, as they became prevalent globally in regions where P. falciparum malaria was endemic. Heterozygous or carrier states conferred a survival advantage; however, doubly heterozygous or homozygous states cause severe hemolytic anemia and multi-organ complications. These disorders are somewhat unique in that all humans have alternate genes for fetal globin chains, which are expressed in fetal life but are silenced on a developmental clock in infancy. An established approach to ameliorating conditions of abnormal adult globin genes is to reactivate, or increase expression, of the endogenous fetal globin genes to replace the missing protein chains in beta thalassemias or inhibit polymerization of hemoglobin S and reduce the red cell abnormalities. This review provides a high-level overview of cell and molecular mechanisms that mediate fetal to adult globin gene switching and pharmacologic therapies that can reactivate fetal globin through different actions. Intermittent or metronomic dosing regimens have overcome challenges of undesirable off-target effects by agents that cause erythroid cell growth arrest. Multiple pharmacologic candidates reactivate or increase the expression of fetal globin protein and proportions of red blood cells containing HbF (F-cells). Hydroxyurea maintains high levels of HbF if begun in infancy, with some decline in mid-childhood. It elicits lower responses in HbF in adult patients, but still has broad clinical benefit in reducing many complications. However, many adult patients do not tolerate optimal hydroxyurea dosing due to cytopenias. Parenterally administered therapies with differing molecular actions, such as demethylating agents and histone deacetylase inhibitors, have shown proof-of-principle in reactivating HbF. Orally bioavailable candidates with complementary molecular mechanisms are in trials. Combining fetal globin-inducing agents with other therapies with complementary mechanisms, such as recombinant erythropoietin that promotes the survival of red blood cells and therapeutics that promote erythroid cell metabolism, should have additive effects. These pharmaceutical candidates offer great clinical potential and global feasibility for ameliorating these serious diseases.
2024-04-01 | Pulmonary Hypertension in Sickle Cell Disease: Novel Findings of Gene Polymorphisms Related to Pathophysiology
Pulmonary hypertension (PH) is a progressive and potentially fatal complication of sickle cell disease (SCD) affecting 6-10% of adult SCD patients. Various mechanisms and theories have been evaluated to explain the pathophysiology of the disease. However, questions remain, particularly regarding the clinical heterogeneity of the disease in terms of symptoms, complications, and survival. Beyond the classical mechanisms that have been thoroughly investigated and include hemolysis, nitric oxide availability, endothelial disorders, thrombosis, and left heart failure, attention is focused nowadays on the potential role of the genes involved in such processes. Potential candidate genes are investigated through next-generation sequencing, with the TGF-β pathway being the initial target. This field of research may also provide novel targets for pharmacologic agents in the future as is already the case with idiopathic PH. The collection and processing of data and samples from multiple centers can yield safe results that will allow a better understanding of SCD-related PH as a part of the disease’s clinical spectrum. The following review attempts to capture the most recent findings of studies on gene polymorphisms that have been associated with PH in SCD patients.
2024-03-23 | Early Administration of Intravenous Hydration and Opioid Analgesics Is Correlated with Decreased Admission Rates during Vaso-Occlusive Episodes in Sickle Cell Disease
Background: Painful vaso-occlusive episodes (VOEs) are the hallmark of sickle cell disease (SCD) and account for frequent visits to the emergency department (ED) or urgent care (UC). Currently, the early administration of analgesics is recommended as initial management; however, there is a need for further understanding of the effect of prompt analgesics and hydration during VOEs. The objective of this study is to analyze the factors associated with the rate of hospital admission in the setting of time to intravenous (IV) analgesics and hydration. Method: This retrospective single-institution study reviewed adult and pediatric patients with SCD who presented with VOEs from January 2018 to August 2023. Results: Of 303 patient encounters, the rates of admission for the overall group, the subgroup which received IV hydration within 60 min of arrival, and the subgroup which received both IV analgesics and hydration within 60 min were 51.8%, 25.6% (RR = 0.46), and 18.2% (RR = 0.33), respectively. Further, factors such as gender and the use of hydroxyurea were found to be significantly associated with the rate of admission. Conclusions: This signifies the importance of standardizing the management of VOEs through the timely administration of IV analgesics and hydration in both adult and pediatric ED/UC.
cell therapies
2023-09-29 | Erythrocytapheresis in Children and Young Adults with Hemoglobinopathies and Iron Overload in Need of Iron Chelation Therapy
Limited data regarding erythrocytapheresis in children, adolescents, and young adults have been published. The aim of this study was to evaluate erythrocytapheresis, either as a standalone therapy or in combination with iron chelation therapy, in children and young adults with hemoglobinopathies in whom current iron chelation therapy is not sufficient in decreasing the iron overload during management. We retrospectively analysed erythrocytapheresis in 19 patients with hemoglobinopathies in need of iron chelation therapy diagnosed with sickle cell disease (SCD) or β-thalassemia major. Patients were divided into (1) a case cohort who received erythrocytapheresis alone or in combination with iron chelation therapy and (2) a control cohort who received oral iron chelation therapy alone. Serum ferritin and haemoglobin levels were compared at five different time points over a one-year period. In the erythrocytapheresis cohort, there was a significant decrease in serum ferritin (p < 0.001). In the iron chelation therapy alone cohort, there was no significant decrease in serum ferritin over time (p = 0.156). Comparing the evolution of median serum ferritin between therapy with erythrocytapheresis and iron chelation therapy showed a statistically significant difference (p = 0.008). Patients with β-thalassemia major receiving erythrocytapheresis showed a greater reduction in serum ferritin compared to patients without (p = 0.036). A difference could not be shown between the erythrocytapheresis and iron chelation single therapies (p = 0.100). This study showed an overall significant reduction in serum ferritin in patients with hemoglobinopathies treated with erythrocytapheresis in addition to iron chelation. A clinical, although not statistical, trend of higher haemoglobin levels was maintained. Erythrocytapheresis in paediatric patients with β-thalassemia major was as effective in decreasing ferritin levels as in previously reported studies with SCD. Erythrocytapheresis is a promising therapy for treating and preventing transfusion-related iron overload.
2023-02-09 | Recent updates of stem cell-based erythropoiesis
Blood transfusions are now an essential part of modern medicine. Transfusable red blood cells (RBCs) are employed in various therapeutic strategies; however, the processes of blood donation, collection, and administration still involve many limitations. Notably, a lack of donors, the risk of transfusion-transmitted disease, and recent pandemics such as COVID-19 have prompted us to search for alternative therapeutics to replace this resource. Originally, RBC production was attempted via the ex vivo differentiation of stem cells. However, a more approachable and effective cell source is now required for broader applications. As a viable alternative, pluripotent stem cells have been actively used in recent research. In this review, we discuss the basic concepts related to erythropoiesis, as well as early research using hematopoietic stem cells ex vivo, and discuss the current trend of in vitro erythropoiesis using human-induced pluripotent stem cells.
2021-05-28 | Prospects for Stem Cell-Based Regenerative Therapies in India
Stem cells offer a promising therapeutic strategy to not only treat several incurable diseases but also regenerate damaged tissues. The current global boom in the field of stem cell and regenerative therapies had led to India becoming a global hotspot for stem cell-based therapies. In this review, we assess the current status of stem cell therapy trials in India and show that the bone marrow-derived stem cells, like mesenchymal stem/stromal cells (MSCs), are predominantly used. Phase 1 and 2 clinical trials have also used MSCs to alleviate symptoms of severe novel coronavirus infections. Recent breakthroughs in gene editing technologies, combined with stem cell therapy, can be effectively harnessed to devise large-scale and affordable treatments for haematological diseases that are highly prevalent in India, like beta-thalassemia and sickle cell diseases. Innovations in stem cell therapy in India can make treatments more affordable to address the needs of in-country patients.
2020-02-17 | Stem cells in the treatment of sickle cell disease
Sickle Cell Disease (SCD) is autosomal recessive disorder that is the result of a point mutation in the coding region of the beta globin gene. Polymerization of red blood cells with the sickle hemoglobin result in painful clinical symptoms and early death due to end organ failure. Improvement of treatment has extended the survival of adolescents into adulthood and offers relief of symptoms but does not offer a cure against the diagnosis being the inevitable cause of an early death. In addition, response to therapies vary between patients depending on their responsiveness and metabolism of medications. Hematopoietic stem cell transplantation offers reduction of recipient Hb S through replacing it with Hb A from the donor. Increased use of hematopoietic stem cell transplantation (HSCT) offers a curative therapy for patients with SCD that have access to an HLA-identical donor. However, limitations to indications for HSCT result due to associated toxicities with myeloablative conditioning and risk of graft failure. Reduced intensity and non-myeloablative conditioning look at reducing associated toxicities and making HSCT readily available for the adult population through mixed chimerism. In addition, clinical trials looking at alternative donors and gene therapies expand the availability of HSCT for the vast majority of patients without an HLA-identical donor.
2019-11-15 | Choice of Donor Source and Conditioning Regimen for Hematopoietic Stem Cell Transplantation in Sickle Cell Disease
In the United States, one out of every 500 African American children have sickle cell disease (SCD), and SCD affects approximately 100,000 Americans. Significant advances in the treatment of this monogenetic disorder have failed to substantially extend the life expectancy of adults with SCD over the past two decades. Hematopoietic stem cell transplantation (HSCT) remains the only curative option for patients with SCD. While human leukocyte antigen (HLA) matched sibling HSCT has been successful, its availability is extremely limited. This review summarizes various conditioning regimens that are currently available. We explore recent efforts to expand the availability of allogeneic HSCT, including matched unrelated, umbilical cord blood, and haploidentical stem cell sources. We consider the use of nonmyeloablative conditioning and haploidentical donor sources as emerging strategies to expand transplant availability, particularly for SCD patients with complications and comorbidities who can undergo neither matched related transplant nor myeloablative conditioning. Finally, we show that improved conditioning agents have improved success rates not only in the HLA-matched sibling setting but also alternative donor settings.
gene therapies
2024-06-10 | CRISPR RNA-Guided Gene Editing and its Clinical Research Applications in Hematology with Focus on Inherited Germline Predisposition to Hematologic Malignancies
Clustered regularly interspaced short palindromic repeats (CRISPR) based gene-editing has begun to transform the treatment landscape of genetic diseases. The history of the discovery of CRISPR/CRISPR-associated (Cas) proteins/single guide RNA (sgRNA)-based gene-editing since the first report of repetitive sequences of unknown significance in 1987 is fascinating, instructive, and inspiring for future advances. The recent approval of CRISPR-Cas9-based gene therapy to treat patients with severe sickle cell anemia and transfusion-dependent beta thalassemia has renewed hope for treating other hematologic diseases, including patients with germline predisposition to hematologic malignancies, who would benefit greatly from the development of CRISPR-based gene therapies. The purpose of this manuscript is three-fold: first, a chronological description of the history of CRISPR-Cas9-sgRNA-based gene editing; second, a brief description of the current state of clinical research in hematologic diseases, including selected applications in treating hematologic diseases with CRISPR-based gene therapy; and third, the current progress in gene therapies in inherited hematologic diseases and bone marrow failure syndromes, to hopefully stimulate efforts towards developing these therapies for patients with inherited bone marrow failure syndromes and other inherited conditions with germline predisposition to hematologic malignancies.
2024-04-18 | Applications of gene modification technologies in the treatment of inherited diseases
Introduction and Purpose: In last years gene modification technologies such as CRISPR/Cas9 has had a revolutionary impact on the treatment of inherited diseases. Technologies developed from bacterial defense mechanisms, has become a basic tools in scientific research and medical therapies. In our article we provided an overview of applications of gene modifications technologies, directly focusing on CRISPR/Cas9, in genetic disease treatment.
State of Knowledge: New applications of CRISPR/Cas9 are still being explored. Treating inherited diseases such as cystic fibrosis, Duchenne muscular dystrophy, thalassemia, hemophilia, Huntington's disease, Crigler-Najjar syndrome, sickle cell anemia, Marfan syndrome, and phenylketonuria, is feasible with this novel technique. A comparative analysis with other gene editing methods highlights CRISPR/Cas9's efficacy, ease of use, and multiplexing capabilities.
Summary: CRISPR/Cas9 is a groundbreaking technology with broad applications in genetic research and therapy. Its ease of use, cost-effectiveness, and ability to target multiple genes simultaneously position it as a preferred method. However, there are some challenges associated with precision issues and ethical considerations in human embryo gene editing. As CRISPR/Cas9 continues to evolve, responsible application and ethical considerations are important for maximizing its potential in treatment of genetic diseases.
2024-04-06 | Impact of hospitalized vaso-occlusive crises in the previous calendar year on mortality and complications in adults with sickle cell disease: a French population-based study
BackgroundHistorically, sickle cell disease (SCD) patients experiencing frequent hospitalized vaso-occlusive crises (HVOC) have been associated with increased mortality, yet recent data reflecting the widespread use of hydroxyurea and advancements in disease management remain limited. Our study aims to assess the association between HVOC and mortality or severe complications in patients with SCD in this new treatment landscape.MethodsThis was a retrospective observational cohort study using the French national health data system. Between 01-01-2012 and 12-31-2018, all SCD patients ≥16 years old (ICD-10 codes D57.0–2) were included and followed until 12-31-2018. HVOC was defined as a hospitalization of ≥1 night with primary diagnosis of SCD with crisis, following an emergency room visit. The association between HVOC and severe complications was assessed with a Cox proportional hazards model.FindingsIn total, 8018 patients (56.6% females; 4538/8018) were included. The 2018 SCD standardized one-year period prevalence was 17.9 cases/100,000 person-years [17.4; 18.3]. The mean rate was 0.84 (1.88) HVOC/person-year. In 2018, 70% (5323/7605), 22% (1671/7605), and 8% (611/7605) of patients experienced 0, 1–2, or 3+ HVOCs, respectively. The median survival time between HVOCs was 415 days [386; 439]. Overall, 312 patients died (3.9%) with a mean age of 49.8 (19.4). Compared to patients without HVOC, the hazard ratios of death in patients with 1–2 or 3+ HVOCs the year prior to death were 1.67 [1.21; 2.30] and 3.70 [2.30; 5.93], respectively. Incidence of acute chest syndrome, pulmonary embolism, osteonecrosis, and sepsis increased with the HVOCs category, but not stroke. In 2018, 29.5% (180/611) of patients with 3+ HVOCs did not take hydroxyurea.InterpretationPatients must be closely monitored during their hospitalizations to intensify treatment and check treatment compliance. Innovative therapies are also required.FundingThe study was funded by Novartis.
2024-02-15 | The Italian breakthrough in CRISPR trials for rare diseases: a focus on beta-thalassemia and sickle cell disease treatment
The development of gene therapy and the current advantageous method of clustered regularly interspaced short palindromic repeats (CRISPRs) has allowed the implementation of several clinical trials aimed at studying the possible efficacy of gene therapy for rare diseases. Rare diseases pose a global challenge, in that their collective impact on health systems is considerable, whereas their individually rare occurrence hinders research and development of efficient therapies. Despite the low prevalence of individual rare diseases, there are more than 7,000 defined rare diseases affecting 3.5–5.9% of the global population. Rare diseases are mostly chronic and approximately 80% are caused by genetic mutation with an early-life onset. In Italy, in 2021 were recorded more than 400,000 people with rare disease. Because of its location and history, Italy has an unfortunate statistic regarding the presence and prevalence of two rare genetic diseases, namely beta-thalassemia, of which there are about 90 million carriers worldwide, 400,000 of whom are actually affected, and sickle cell disease, with about 300 million carriers and 6.5 million people affected worldwide. Advancements in genomic studies allowed Italy to join clinical trials to study effective and resolving gene therapies for BT and SCD. This study reports on the impact of rare diseases in Italy, ongoing studies, and recent achievements in BT and SCD trials using the CRISPR method and remaining hurdles in the application of CRISPR technology to rare diseases, also taking a glimpse at the newest challenges and future opportunities in the genetic treatment for rare diseases.
2023-09-20 | Global Trends on β-thalassemia Research over 10 Years: A Bibliometric Analysis
Abstract Introduction Thalassemia, an inherited quantitative globin disorder, is the most prevalent monogenic disease globally. While severe alpha thalassemia results in intrauterine death, β-thalassemia manifests during childhood due to the "second conversion of hemoglobin," garnering increased attention in recent decades. Methods In this study, a bibliometric analysis will be conducted of thalassemia articles published in the Web of Science Core Collection database between 2013 and 2023 to establish a comprehensive overview and to identify emerging trends. A total of 5655 studies published between 2013 and 2023 were systematically retrieved, and annual publications demonstrated a steady increase, maintaining a high level over the past decade. Results The United States contributed the highest number of publications, followed by China. Notably, the journal Blood emerged as the leading authority in β-thalassemia research. Analysis of research hotspots revealed that the pathogenesis of β-thalassemia is primarily linked to iron overload, anemia, gene mutations, and ineffective erythropoiesis. Furthermore, recent studies focusing on gene editing therapies present promising avenues for future investigation. Conclusion These findings grasp the research status of β-thalassemia and shed new light on future research frontiers.
antibodies
2023-04-01 | 5588995 COMPARATIVE EFFICACY AND SAFETY OF PHARMACOLOGICAL INTERVENTIONS FOR SICKLE CELL DISEASE IN CHILDREN AND ADOLESCENTS: A NETWORK META-ANALYSIS
Background: Sickle cell disease (SCD), an inherited hemoglobinopathy characterized by anemia, severe pain, acute chest syndrome (ACS) and vaso-occlusive crisis (VOC), has important impact on morbidity and mortality worldwide, especially in the pediatric population (over 50% die before age of 5). Although few treatment options are available, new disease modifying therapies, intended to prevent or reduce SCD-related complications are under development. Previous systematic reviews are limited to adult patients or focused only on gathering data of few therapies. Aims: Our aim was to synthetize the evidence on the efficacy and safety profiles of pharmacological interventions for managing SCD in children and adolescents. Methods: A systematic review with searches in PubMed, Scopus, and Web of Science was performed (May-2022). The protocol is registered at PROSPERO CRD42022328471. We included randomized controlled trials comparing any disease-modifying agent used to treat SCD complications in patients under 18 years old. The outcomes of interest included: VOC, ACS, transfusions, hospital admission, discontinuation, serious adverse events. Data were pooled by means of Bayesian network meta-analyses with surface under the cumulative ranking curve analyses (SUCRA). Results were reported as odds ratio (OR) with 95% credibility intervals (CrI). Additionally, stochastic multicriteria acceptability analyses (SMAA) were performed. The methodological quality of the trials and certainty of evidence were evaluated through RoB 2.0 tool and GRADE approach, respectively. Results: Overall, 17 randomized controlled trials (n=1,972 patients) published between 1982-2022, conducted mostly in Africa (41%) and North America (35%) were included for analyses. Around one-third of the trials were restricted to homozygous patients for the SCD allele (SS HMZ); yet when reported, patients with heterozygous S-C combination represented less than 30% of the population. Males accounted for 49.0% of the cases, with ages varying from 1-19 years old. Almost all trials (n=15, 88.2%) directly compared active drugs with placebo. The evaluated interventions were: hydroxyurea [n=6 trials], L-arginine [n=3], antiplatelets [n=2], immunotherapy/monoclonal antibodies [n=2], sulphates [n=2], docosahexaenoic acid [n=1], niprisan [n=1] (Figure 1). SUCRA and SMAA revealed that immunotherapy/monoclonal antibodies and hydroxyurea 20 mg/kg are potentially more effective against ACS (17% and 24% probabilities, respectively), VOC (around 29% and 20%, respectively) and needing of transfusions (around 25%), while L-arginine (100-200 mg/kg) and placebo were more associated with these events. Although therapies were overall considered safe, antiplatelet and sulfates may lead to more discontinuations and severe adverse events (uncertainty evidence). Results were similar between age subgroups (<10 years vs. 10-19 years). Summary - Conclusion: The available evidence on the effect of drugs for managing SCD in children and adolescents is still insufficient and weak. No clear definition and reporting criteria for some outcomes exist. Hydroxyurea 20 mg/kg/day may remain the standard of care for these patients, however, long-term, well-designed trials comparing new immunotherapy/monoclonal antibodies should be performed. The use of monotherapies with L-arginine, antiplatelets or sulphates should be avoided given the poor benefit-risk ratio for this population.References 1. Brandow et al, J Hematol Oncol 2022; 15(1):20 2. Quinn et al, Pediatr Blood Cancer 2022; 69(8):e29805 3. Tonin et al, Pharm Pract (Granada) 2017; 15(1):943
2023-01-25 | A cross-sectional study on pain management during vaso-occlusive crisis in sickle cell disease
Background: Sickle cell disease is an inherited hematological disorder characterized by hard and sticky red blood cells that appears like a C-shaped “sickle” in contrast to the healthy, round red blood cells which tend to stick and clog the blood vessels during blood flow leading to pain or vaso-occlusive crisis. Methods: A cross-sectional study was conducted at Yashoda hospital in Hyderabad, India. Data regarding the management of acute pain during VOC in SCD patients was gathered from the hematology department on a daily basis during the duration of the study. The data was recorded in an online questionnaire form and a subsequent DUE was conducted. Results: Among all the patients that were enrolled in the study, acute pain as VOC was presented in 72%, whereas 28% did not experience pain. Pain was manifested as acute chest syndrome, generalized body pain, headache. Crizanlizumab, a monoclonal antibody was administered to patients who were ≥16 years to decrease the frequency of VOC. Upon DUE, per prescription distribution of crizanlizumab was 11.2%, while 88.8% constituted of anti-metabolites, antibiotics, analgesics, opiate antagonist, etc. Frequency of use of crizanlizumab among SCD patients was 69.23% Conclusions: Management of VOC cannot be described as one size fits all. Interindividual variability must be considered at all times during planning and implementing a treatment regimen. Assessment of pain on pain scale to ensure targeted treatment at maximum effective concentration followed by titration of dose to reduce the occurrence of tolerance, withdrawal, dependence and addiction should be basis of management.
2017-08-23 | Pathways to pulmonary hypertension in sickle cell disease: the search for prevention and early intervention
Pulmonary hypertension (PH) develops in a significant number of patients with sickle cell disease (SCD), resulting in increased morbidity and mortality. This review focuses on PH pathophysiology, risk stratification, and new recommendations for screening and treatment for patients with SCD. Areas covered: An extensive PubMed literature search was performed. While the pathophysiology of PH in SCD is yet to be fully deciphered, it is known that the etiology is multifactorial; hemolysis, hypercoagulability, hypoxemia, ischemic-reperfusion injury, oxidative stress, and genetic susceptibility all contribute in varying degrees to endothelial dysfunction. Hemolysis, in particular, seems to play a key role by inciting an imbalance in the regulatory axis of nitric oxide and arginine metabolism. Systematic risk stratification starting in childhood based on clinical features and biomarkers that enable early detection is necessary. Multi-faceted, targeted interventions, before irreversible vasculopathy develops, will allow for improved patient outcomes and life expectancy. Expert commentary: Despite progress in our understanding of PH in SCD, clinically proven therapies remain elusive and additional controlled clinical trials are needed. Prevention of disease starts in childhood, a critical window for intervention. Given the complex and multifactorial nature of SCD, patients will ultimately benefit from combination therapies that simultaneously targets multiple mechanisms.
2017-03-08 | Evaluation of anti-inflammatory response in sickle cell anemia patients
Background and objective: Inflammation has been implicated in the pathogenesis of most complications seen in Sickle cell anemia (SCA) patients.This project aimed to evaluate serum levels of two newly discovered anti-inflammatory cytokines IL-27 and IL-37 and some pro-inflammatory cytokines among Brazilian SCA patients that are hydroxurea-naive and compared with hydroxyurea-treated patients and HbAA controls.Furthermore, to demonstrate the effect of IL-27, IL-37 and heme on in vitro secretion of IL-8 in human neutrophils and monocytes.Methods: It is a cross-sectional study of 82 consenting SCA (35 hydroxyureanaïve HbSS and 47 hydroxyurea-treated HbSS) patients in steady state and 49 HbAA consenting individuals.Their clinical details were obtained by interview and from patients' records.The serum levels of IL-27, IL-37, TGF-β, TNF-α, IL-1β, IL-6 and IL-8 were quantified by ELISA.Neutrophils and monocytes were isolated from healthy controls, cultured separately without or with cytokines (IL-27 and IL-37) and heme.The pro-inflammatory cytokines in the supernatant were detected by ELISA, Results: Serum levels of IL-27, IL-37, IL-1β, IL-6 and IL-8 in hydroxyurea-naïve SCA patients were significantly elevated compared to HbAA controls There was no significant difference in the serum levels of both anti-and pro-inflammatory cytokines except IL-8 in the HU-treated SCA patients compared to controls.IL-27 and IL-37 were positively correlated in both HU-naive and hydroxyurea-treated HbSS patients.In vitro IL-8 production by IL-27 and IL-37 pre-treated neutrophils and monocytes was significantly inhibited despite addition of heme.Conclusions: Our findings show that IL-27 and IL-37 are elevated in HU-naïve patients.The study support that the use of HU did not significantly alter serum levels of anti-and pro-inflammatory cytokines except IL-8 in SCA patients.IL-27 and IL-37 may play a regulatory role on the pro-inflammatory pathways, as suggested by the in vitro studies.This role is probably sufficient to prevent further cellular or tissue damage but not potent enough to prevent inflammation.Thus, IL-27 and IL-37 may be potential immuno-targets to ameliorate complications associated with elevated heme as seen in SCA and other hemolytic anemias.
2016-10-21 | BILATERAL CHOROIDAL NEOVASCULARIZATION IN A PATIENT WITH BETA-THALASSEMIA MAJOR AND ITS MANAGEMENT
Purpose: To describe a case of bilateral choroidal neovascularization in a patient with beta-thalassemia major and an interventional therapeutic attempt. Method: Retrospective case report. Result: A known case of beta-thalassemia major presented with gradual vision loss. Fundoscopy revealed bilateral macular edema accompanied by intraretinal hemorrhages. Optical coherence tomography and fluorescein angiography were compatible with the diagnosis of choroidal neovascularization. No signs of angioid streaks or other related abnormalities were noticed in examination and imaging. The patient was treated with intravitreal bevacizumab, and visual acuity improved within 6 months of follow-up. Conclusion: Bilateral choroidal neovascularization can be a presenting pathology in patients with beta-thalassemia major. Anti–vascular endothelial growth factor is a promising treatment option.
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2024-02-08 | Beta-Thalassemia: A Pharmacological Drug-Based Treatment
This review was performed to determine the potential of drugs that can remove or decrease the requirements for blood transfusion among beta (β)-thalassemia patients. A comprehensive literature search was conducted to identify clinical trials and studies using PubMed Central, Google Scholar, PubMed, and ScienceDirect archived articles published from 1996 to November 2023. According to this review, clinical trials for a number of drugs, including luspatercept, sotatercept, mitapivat, etavopivat, hydroxyurea, rapamycin, decitabine, thalidomide, and quercetin, have been performed as part of efforts to improve the cure strategy for β-thalassemia. Of these drugs, luspatercept and sotatercept have exhibited particularly promising results and have been granted US Food and Drug Administration (FDA) approval for use in β-thalassemia patients. The mode of action for the drugs luspatercept and sotatercept involves the stimulation of hemoglobin (Hb) production or enhancement of its functionality, thereby decreasing reliance on blood transfusions and enhancing the overall quality of life. In this way, drugs like luspatercept and sotatercept present an opportunity to notably decrease the necessity for blood transfusions in β-thalassemia patients, improving their standard of living and overall prognosis. However, more research is needed to evaluate the effectiveness and safety of these drugs in the long run.
2022-05-12 | Targeting Genetic Modifiers of HBG Gene Expression in Sickle Cell Disease: The miRNA Option
Sickle cell disease (SCD) is one of the most common inherited hemoglobinopathy disorders that affects millions of people worldwide. Reactivation of HBG (HBG1, HBG2) gene expression and induction of fetal hemoglobin (HbF) is an important therapeutic strategy for ameliorating the clinical symptoms and severity of SCD. Hydroxyurea is the only US FDA-approved drug with proven efficacy to induce HbF in SCD patients, yet serious complications have been associated with its use. Over the last three decades, numerous additional pharmacological agents that reactivate HBG transcription in vitro have been investigated, but few have proceeded to FDA approval, with the exception of arginine butyrate and decitabine; however, neither drug met the requirements for routine clinical use due to difficulties with oral delivery and inability to achieve therapeutic levels. Thus, novel approaches that produce sufficient efficacy, specificity, and sustainable HbF induction with low adverse effects are desirable. More recently, microRNAs (miRNAs) have gained attention for their diagnostic and therapeutic potential to treat various diseases ranging from cancer to Alzheimer’s disease via targeting oncogenes and their gene products. Thus, it is plausible that miRNAs that target HBG regulatory genes may be useful for inducing HbF as a treatment for SCD. Our laboratory and others have documented the association of miRNAs with HBG activation or suppression via silencing transcriptional repressors and activators, respectively, of HBG expression. Herein, we review progress made in understanding molecular mechanisms of miRNA-mediated HBG regulation and discuss the extent to which molecular targets of HBG might be suitable prospects for development of SCD clinical therapy. Lastly, we discuss challenges with the application of miRNA delivery in vivo and provide potential strategies for overcoming barriers in the future.
2019-05-17 | Potential Therapeutic Modalities of Reawakening Fetal Hemoglobin Simulated by Reaction Systems
Thalassemia syndromes are a diverse group of inherited genetic disorders.There are different types of thalassemia disorders, such as, β-thalassemia, which is also called Mediterranean anemia, that is an inherited disease that played a major role in the American thriller movie, "Dying of the light" starring Nicolas Cage (Dec.2014).In this study, we focus on the beta-globin (β-globin) gene family related disorders.We seek potential amelioration strategies for β-thalassemia and sickle cell anemia via γ-globin gene induction.In this work, a simulation model is developed, utilizing a reaction systems methodology.These systems are finite and based on a discrete time scale and can be used to describe and analyze complex biological systems and biological phenomenon.In our model, simulations of normal and abnormal cases of fetal, to adult hemoglobin switching developmental stage are illustrated.Various types of known and potential treatment strategies for β-thalassemia and sickle cell anemia cases from the literature have been utilized to validate our model, used for identifying new potential treatments to be tested by molecular biologists, in the future studies.Moreover, we propose a novel potential simulation, as a therapeutic means, for β-thalassemia and sickle cell anemia, by identifying FOG1 as a potential target.Finally, our proposed model, based on a reaction systems methodology, shows that inhibition of FOG1 expression by using methods, such as, RNAi induces γ-globin gene expression and can compensate for the lack of beta-globin in patients suffering from β-globin gene related diseases, such as, β-thalassemia and sickle cell anemia.
2013-02-21 | Hemolysis and free hemoglobin revisited: exploring hemoglobin and hemin scavengers as a novel class of therapeutic proteins
Abstract Hemolysis occurs in many hematologic and nonhematologic diseases. Extracellular hemoglobin (Hb) has been found to trigger specific pathophysiologies that are associated with adverse clinical outcomes in patients with hemolysis, such as acute and chronic vascular disease, inflammation, thrombosis, and renal impairment. Among the molecular characteristics of extracellular Hb, translocation of the molecule into the extravascular space, oxidative and nitric oxide reactions, hemin release, and molecular signaling effects of hemin appear to be the most critical. Limited clinical experience with a plasma-derived haptoglobin (Hp) product in Japan and more recent preclinical animal studies suggest that the natural Hb and the hemin-scavenger proteins Hp and hemopexin have a strong potential to neutralize the adverse physiologic effects of Hb and hemin. This includes conditions that are as diverse as RBC transfusion, sickle cell disease, sepsis, and extracorporeal circulation. This perspective reviews the principal mechanisms of Hb and hemin toxicity in different disease states, updates how the natural scavengers efficiently control these toxic moieties, and explores critical issues in the development of human plasma–derived Hp and hemopexin as therapeutics for patients with excessive intravascular hemolysis.
2006-12-21 | Silencing and reactivation of gamma-globin expression in humans
A new erythroblastic leukemia cell line (EEB) was established from a patient with early erythroblastic leukemia. The cells had features of immature erythroblasts, including an agranular basophilic cytoplasm and CD36, CD71, CD175s (sialyl-Tn) and CD235a (glycophorin A) expression without CD41 expression, myeloperoxidase activity and platelet-peroxidase activity. The cells were confirmed to be of the erythroid lineage based on expression of the gamma-globin message. They were induced to differentiate into benzidine-positive cells by hemin and δ-amino levulinic acid (δ-ALA). An analysis of cell membrane lipids showed that EEB cells contain a type of glycerolipid, phosphatidylglucose (PhGlc), but not unbranched type 2 chains, i antigens. GL-7 which is a recombinant Fab fragment of GL-2 and binds to PhGlc, induced production of hemoglobin F (HbF) associated with accumulation of the gamma-globin (γ-globin) message in EEB cells. The GL-7-mediated erythroid differentiation was associated with apoptosis. These results suggest that direct signaling to PhGlc mediates erythroid differentiation and apoptosis in EEB cells.
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Drug Discovery Landscape
1 orphan drug designation for Sickle cell-beta-thalassemia disease syndrome.
1 orphan drug designation for Sickle cell-beta-thalassemia disease syndrome.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Isobutyramide | small molecules | FDA | — | Alpha Therapeutic Corporation |
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