-
Journal of Hematology & Oncology Mar 2022Sickle cell disease (SCD), which affects approximately 100,000 individuals in the USA and more than 3 million worldwide, is caused by mutations in the βb globin gene... (Review)
Review
Sickle cell disease (SCD), which affects approximately 100,000 individuals in the USA and more than 3 million worldwide, is caused by mutations in the βb globin gene that result in sickle hemoglobin production. Sickle hemoglobin polymerization leads to red blood cell sickling, chronic hemolysis and vaso-occlusion. Acute and chronic pain as well as end-organ damage occur throughout the lifespan of individuals living with SCD resulting in significant disease morbidity and a median life expectancy of 43 years in the USA. In this review, we discuss advances in the diagnosis and management of four major complications: acute and chronic pain, cardiopulmonary disease, central nervous system disease and kidney disease. We also discuss advances in disease-modifying and curative therapeutic options for SCD. The recent availability of L-glutamine, crizanlizumab and voxelotor provides an alternative or supplement to hydroxyurea, which remains the mainstay for disease-modifying therapy. Five-year event-free and overall survival rates remain high for individuals with SCD undergoing allogeneic hematopoietic stem cell transplant using matched sibling donors. However, newer approaches to graft-versus-host (GVHD) prophylaxis and the incorporation of post-transplant cyclophosphamide have improved engraftment rates, reduced GVHD and have allowed for alternative donors for individuals without an HLA-matched sibling. Despite progress in the field, additional longitudinal studies, clinical trials as well as dissemination and implementation studies are needed to optimize outcomes in SCD.
Topics: Anemia, Sickle Cell; Chronic Pain; Graft vs Host Disease; Hemoglobin, Sickle; Humans; Hydroxyurea
PubMed: 35241123
DOI: 10.1186/s13045-022-01237-z -
Blood Nov 2020Fetal hemoglobin (HbF) can blunt the pathophysiology, temper the clinical course, and offer prospects for curative therapy of sickle cell disease. This review focuses on... (Review)
Review
Fetal hemoglobin (HbF) can blunt the pathophysiology, temper the clinical course, and offer prospects for curative therapy of sickle cell disease. This review focuses on (1) HbF quantitative trait loci and the geography of β-globin gene haplotypes, especially those found in the Middle East; (2) how HbF might differentially impact the pathophysiology and many subphenotypes of sickle cell disease; (3) clinical implications of person-to-person variation in the distribution of HbF among HbF-containing erythrocytes; and (4) reactivation of HbF gene expression using both pharmacologic and cell-based therapeutic approaches. A confluence of detailed understanding of the molecular basis of HbF gene expression, coupled with the ability to precisely target by genomic editing most areas of the genome, is producing important preliminary therapeutic results that could provide new options for cell-based therapeutics with curative intent.
Topics: Anemia, Sickle Cell; Fetal Hemoglobin; Gene Editing; Gene Expression Regulation; Gene Knockdown Techniques; Genetic Therapy; Genetic Vectors; Haplotypes; Humans; Hydroxyurea; Lentivirus; Microfilament Proteins; Polymorphism, Single Nucleotide; Proto-Oncogene Proteins c-myb; Quantitative Trait Loci; RNA Interference; RNA, Small Interfering; Receptors, Cell Surface; Repressor Proteins; Stroke; beta-Globins; gamma-Globins
PubMed: 32808012
DOI: 10.1182/blood.2020007645 -
Blood Apr 2023Sickle cell disease (SCD) is a monogenic disease caused by a nucleotide mutation in the β-globin gene. Current gene therapy studies are mainly focused on lentiviral...
Sickle cell disease (SCD) is a monogenic disease caused by a nucleotide mutation in the β-globin gene. Current gene therapy studies are mainly focused on lentiviral vector-mediated gene addition or CRISPR/Cas9-mediated fetal globin reactivation, leaving the root cause unfixed. We developed a vectorized prime editing system that can directly repair the SCD mutation in hematopoietic stem cells (HSCs) in vivo in a SCD mouse model (CD46/Townes mice). Our approach involved a single intravenous injection of a nonintegrating, prime editor-expressing viral vector into mobilized CD46/Townes mice and low-dose drug selection in vivo. This procedure resulted in the correction of ∼40% of βS alleles in HSCs. On average, 43% of sickle hemoglobin was replaced by adult hemoglobin, thereby greatly mitigating the SCD phenotypes. Transplantation in secondary recipients demonstrated that long-term repopulating HSCs were edited. Highly efficient target site editing was achieved with minimal generation of insertions and deletions and no detectable off-target editing. Because of its simplicity and portability, our in vivo prime editing approach has the potential for application in resource-poor countries where SCD is prevalent.
Topics: Mice; Animals; Gene Editing; CRISPR-Cas Systems; Anemia, Sickle Cell; Hematopoietic Stem Cells; Hemoglobin, Sickle
PubMed: 36800642
DOI: 10.1182/blood.2022018252 -
Frontiers in Immunology 2020Sickle cell disease (SCD) is a genetic disease caused by a single mutation in the β-globin gene, leading to the production of an abnormal hemoglobin called hemoglobin S... (Review)
Review
Sickle cell disease (SCD) is a genetic disease caused by a single mutation in the β-globin gene, leading to the production of an abnormal hemoglobin called hemoglobin S (HbS), which polymerizes under deoxygenation, and induces the sickling of red blood cells (RBCs). Sickled RBCs are very fragile and rigid, and patients consequently become anemic and develop frequent and recurrent vaso-occlusive crises. However, it is now evident that SCD is not only a RBC rheological disease. Accumulating evidence shows that SCD is also characterized by the presence of chronic inflammation and oxidative stress, participating in the development of chronic vasculopathy and several chronic complications. The accumulation of hemoglobin and heme in the plasma, as a consequence of enhanced intravascular hemolysis, decreases nitric oxide bioavailability and enhances the production of reactive oxygen species (ROS). Heme and hemoglobin also represent erythrocytic danger-associated molecular pattern molecules (eDAMPs), which may activate endothelial inflammation through TLR-4 signaling and promote the development of complications, such as acute chest syndrome. It is also suspected that heme may activate the innate immune complement system and stimulate neutrophils to release neutrophil extracellular traps. A large amount of microparticles (MPs) from various cellular origins (platelets, RBCs, white blood cells, endothelial cells) is also released into the plasma of SCD patients and participate in the inflammation and oxidative stress in SCD. In turn, this pro-inflammatory and oxidative stress environment further alters the RBC properties. Increased pro-inflammatory cytokine concentrations promote the activation of RBC NADPH oxidase and, thus, raise the production of intra-erythrocyte ROS. Such enhanced oxidative stress causes deleterious damage to the RBC membrane and further alters the deformability of the cells, modifying their aggregation properties. These RBC rheological alterations have been shown to be associated to specific SCD complications, such as leg ulcers, priapism, and glomerulopathy. Moreover, RBCs positive for the Duffy antigen receptor for chemokines may be very sensitive to various inflammatory molecules that promote RBC dehydration and increase RBC adhesiveness to the vascular wall. In summary, SCD is characterized by a vicious circle between abnormal RBC rheology and inflammation, which modulates the clinical severity of patients.
Topics: Anemia, Sickle Cell; Animals; Duffy Blood-Group System; Erythrocytes; Extracellular Traps; Hemoglobin, Sickle; Hemolysis; Humans; Inflammation; Mice; Oxidative Stress; Reactive Oxygen Species; Receptors, Cell Surface
PubMed: 32231672
DOI: 10.3389/fimmu.2020.00454 -
Micromachines May 2021Sickle cell disease (SCD) is a widespread disease caused by a mutation in the beta-globin gene that leads to the production of abnormal hemoglobin called hemoglobin S.... (Review)
Review
Sickle cell disease (SCD) is a widespread disease caused by a mutation in the beta-globin gene that leads to the production of abnormal hemoglobin called hemoglobin S. The inheritance of the mutation could be homozygous or heterozygous combined with another hemoglobin mutation. SCD can be characterized by the presence of dense, sickled cells that causes hemolysis of blood cells, anemia, painful episodes, organ damage, and in some cases death. Early detection of SCD can help to reduce the mortality and manage the disease effectively. Therefore, different techniques have been developed to detect the sickle cell disease and the carrier states with high sensitivity and specificity. These techniques can be screening tests such as complete blood count, peripheral blood smears, and sickling test; confirmatory tests such as hemoglobin separation techniques; and genetic tests, which are more expensive and need to be done in centralized labs by highly skilled personnel. However, advanced portable point of care techniques have been developed to provide a low-cost, simple, and user-friendly device for detecting SCD, for instance coupling solubility tests with portable devices, using smartphone microscopic classifications, image processing techniques, rapid immunoassays, and sensor-based platforms. This review provides an overview of the current and emerging techniques for sickle cell disease detection and highlights the different potential methods that could be applied to help the early diagnosis of SCD.
PubMed: 34063111
DOI: 10.3390/mi12050519 -
The New England Journal of Medicine Jan 2021Sickle cell disease is characterized by hemolytic anemia, pain, and progressive organ damage. A high level of erythrocyte fetal hemoglobin (HbF) comprising α- and... (Clinical Trial)
Clinical Trial
BACKGROUND
Sickle cell disease is characterized by hemolytic anemia, pain, and progressive organ damage. A high level of erythrocyte fetal hemoglobin (HbF) comprising α- and γ-globins may ameliorate these manifestations by mitigating sickle hemoglobin polymerization and erythrocyte sickling. is a repressor of γ-globin expression and HbF production in adult erythrocytes. Its down-regulation is a promising therapeutic strategy for induction of HbF.
METHODS
We enrolled patients with sickle cell disease in a single-center, open-label pilot study. The investigational therapy involved infusion of autologous CD34+ cells transduced with the BCH-BB694 lentiviral vector, which encodes a short hairpin RNA (shRNA) targeting mRNA embedded in a microRNA (shmiR), allowing erythroid lineage-specific knockdown. Patients were assessed for primary end points of engraftment and safety and for hematologic and clinical responses to treatment.
RESULTS
As of October 2020, six patients had been followed for at least 6 months after receiving BCH-BB694 gene therapy; median follow-up was 18 months (range, 7 to 29). All patients had engraftment, and adverse events were consistent with effects of the preparative chemotherapy. All the patients who could be fully evaluated achieved robust and stable HbF induction (percentage HbF/(F+S) at most recent follow-up, 20.4 to 41.3%), with HbF broadly distributed in red cells (F-cells 58.9 to 93.6% of untransfused red cells) and HbF per F-cell of 9.0 to 18.6 pg per cell. Clinical manifestations of sickle cell disease were reduced or absent during the follow-up period.
CONCLUSIONS
This study validates BCL11A inhibition as an effective target for HbF induction and provides preliminary evidence that shmiR-based gene knockdown offers a favorable risk-benefit profile in sickle cell disease. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT03282656).
Topics: Adolescent; Adult; Anemia, Sickle Cell; Child; Down-Regulation; Female; Fetal Hemoglobin; Gene Knockdown Techniques; Genetic Therapy; Genetic Vectors; Humans; Male; Pilot Projects; RNA Interference; RNA, Small Interfering; Repressor Proteins; Transplantation, Autologous; Young Adult; gamma-Globins
PubMed: 33283990
DOI: 10.1056/NEJMoa2029392 -
Blood Reviews Nov 2022Sickle cell disease is a very variable condition, with outcomes ranging from death in childhood to living relatively symptom free into the 8 decade. Much of this... (Review)
Review
Sickle cell disease is a very variable condition, with outcomes ranging from death in childhood to living relatively symptom free into the 8 decade. Much of this variability is unexplained. The co-inheritance of α thalassaemia and factors determining HbF levels significantly modify the phenotype, but few other significant genetic variants have been identified, despite extensive studies. Environmental factors are undoubtedly important, with socio-economics and access to basic medical care explaining the huge differences in outcomes between many low- and high-income countries. Exposure to cold and windy weather seems to precipitate acute complications in many people, although these effects are unpredictable and vary with geography. Many studies have tried to identify prognostic factors which can be used to predict outcomes, particularly when applied in infancy. Overall, low haemoglobin, low haemoglobin F percentage and high reticulocytes in childhood are associated with worse outcomes, although again these effects are fairly weak and inconsistent.
Topics: Humans; Fetal Hemoglobin; Anemia, Sickle Cell; Reticulocytes
PubMed: 35750558
DOI: 10.1016/j.blre.2022.100983 -
Medicine Sep 2023Sickle cell disease (SCD) is a hereditary blood disorder characterized by the production of abnormal hemoglobin molecules that cause red blood cells to take on a... (Review)
Review
Sickle cell disease (SCD) is a hereditary blood disorder characterized by the production of abnormal hemoglobin molecules that cause red blood cells to take on a crescent or sickle shape. This condition affects millions of people worldwide, particularly those of African, Mediterranean, Middle Eastern, and South Asian descent. This paper aims to provide an overview of SCD by exploring its causes, symptoms, and available treatment options. The primary cause of SCD is a mutation in the gene responsible for producing hemoglobin, the protein that carries oxygen in red blood cells. This mutation has abnormal hemoglobin called hemoglobin S, which causes red blood cells to become stiff and sticky, leading to various health complications. Patients with SCD may experience recurrent pain, fatigue, anemia, and increased infection susceptibility. Treatment options for SCD focus on managing symptoms and preventing complications. This includes pain management with analgesics, hydration, and blood transfusions to improve oxygen delivery. Hydroxyurea, a medication that increases the production of fetal hemoglobin, is commonly used to reduce the frequency and severity of pain crises. Additionally, bone marrow or stem cell transplants can cure select individuals with severe SCD. Finally, understanding the causes, symptoms, and treatment options for SCD is crucial for healthcare professionals, patients, and their families. It enables early diagnosis, effective symptom management, and improved quality of life for individuals with this chronic condition.
Topics: Humans; Anemia, Sickle Cell; Causality; Erythrocytes; Quality of Life
PubMed: 37746969
DOI: 10.1097/MD.0000000000035237