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The Journal of Clinical Investigation Sep 2023Sickle cell disease (SCD) is a hereditary hemoglobinopathy characterized by painful vaso-occlusive crises (VOC) and chronic hemolysis. The mononuclear phagocyte system...
Sickle cell disease (SCD) is a hereditary hemoglobinopathy characterized by painful vaso-occlusive crises (VOC) and chronic hemolysis. The mononuclear phagocyte system is pivotal to SCD pathophysiology, but the mechanisms governing monocyte/macrophage differentiation remain unknown. This study examined the influence of hemolysis on circulating monocyte trajectories in SCD. We discovered that hemolysis stimulated CSF-1 production, partly by endothelial cells via Nrf2, promoting classical monocyte (CMo) differentiation into blood patrolling monocytes (PMo) in SCD mice. However, hemolysis also upregulated CCL-2 through IFN-I, inducing CMo transmigration and differentiation into tissue monocyte-derived macrophages. Blocking CMo transmigration by anti-P selectin antibody in SCD mice increased circulating PMo, corroborating that CMo-to-tissue macrophage differentiation occurs at the expense of CMo-to-blood PMo differentiation. We observed a positive correlation between plasma CSF-1/CCL-2 ratios and blood PMo levels in patients with SCD, underscoring the clinical significance of these two opposing factors in monocyte differentiation. Combined treatment with CSF-1 and anti-P selectin antibody more effectively increased PMo numbers and reduced stasis compared with single-agent therapies in SCD mice. Altogether, these data indicate that monocyte fates are regulated by the balance between two heme pathways, Nrf2/CSF-1 and IFN-I/CCL-2, and suggest that the CSF-1/CCL-2 ratio may present a diagnostic and therapeutic target in SCD.
Topics: Mice; Animals; Hemolysis; Monocytes; Macrophage Colony-Stimulating Factor; Endothelial Cells; NF-E2-Related Factor 2; Anemia, Sickle Cell; Vascular Diseases; Cell Differentiation; Selectins
PubMed: 37490346
DOI: 10.1172/JCI172087 -
Cells May 2024Sickle cell disease is an orphan disease affecting ethnic minorities and characterized by profound systemic manifestations. Although around 100,000 individuals with SCD... (Review)
Review
Sickle cell disease is an orphan disease affecting ethnic minorities and characterized by profound systemic manifestations. Although around 100,000 individuals with SCD are living in the US, the exact number of individuals is unknown, and it is considered an orphan disease. This single-gene disorder leads to red blood cell sickling and the deoxygenation of hemoglobin, resulting in hemolysis. SCD is associated with acute complications such as vaso-occlusive crisis, infections, and chronic target organ complications such as pulmonary disease and renal failure. While genetic therapy holds promise to alter the fundamental disease process, the major challenge in the field remains the target end organ damage and ways to mitigate or reverse it. Here, we provide an overview of the clinical manifestations and pathogenesis with a focus on end-organ damage and current therapeutic options, including recent FDA-approved stem cell and gene editing therapies.
Topics: Anemia, Sickle Cell; Humans; Genetic Therapy; Gene Editing; Animals
PubMed: 38891066
DOI: 10.3390/cells13110934 -
Molecular Therapy : the Journal of the... May 2024In recent years, a growing number of clinical trials have been initiated to evaluate gene therapy approaches for the treatment of patients with transfusion-dependent... (Review)
Review
In recent years, a growing number of clinical trials have been initiated to evaluate gene therapy approaches for the treatment of patients with transfusion-dependent β-thalassemia and sickle cell disease (SCD). Therapeutic modalities being assessed in these trials utilize different molecular techniques, including lentiviral vectors to add functional copies of the gene encoding the hemoglobin β subunit in defective cells and CRISPR-Cas9, transcription activator-like effector protein nuclease, and zinc finger nuclease gene editing strategies to either directly address the underlying genetic cause of disease or induce fetal hemoglobin production by gene disruption. Here, we review the mechanisms of action of these various gene addition and gene editing approaches and describe the status of clinical trials designed to evaluate the potentially for these approaches to provide one-time functional cures to patients with transfusion-dependent β-thalassemia and SCD.
Topics: Humans; Genetic Therapy; Gene Editing; CRISPR-Cas Systems; Hemoglobinopathies; Genetic Vectors; Clinical Trials as Topic; Anemia, Sickle Cell; beta-Thalassemia; Animals; Lentivirus
PubMed: 38454604
DOI: 10.1016/j.ymthe.2024.03.005 -
JPMA. the Journal of the Pakistan... Dec 2023To detect mutation in cases having haemoglobin A2 level >7% on high performance liquid chromatography.
OBJECTIVE
To detect mutation in cases having haemoglobin A2 level >7% on high performance liquid chromatography.
METHODS
The cross-sectional, descriptive study was conducted from July 2017 to December 2018 at the Department of Haematology and Human Genetics and Molecular Biology, University of Health Sciences, Lahore, Pakistan, and comprised patients of either gender with haemoglobin A2 ≥7%. The samples were collected from different cities of Punjab in collaboration with the Punjab Thalassemia Prevention Programme, Lahore. The samples were subjected to complete blood count and high performance liquid chromatography using automated haematology analysers and variant-II beta thalassemia short programme, respectively. To analyse haemoglobin E mutations at the molecular level, polymerase chain reaction-restriction fragment length polymorphism (PCR_RFLP) was performed using a type IIS restriction endonuclease known as Mnl1 (derived from Moraxella nonliquefaciens) to cleave DNA at specific sites and the results were further confirmed on randomly selected samples using Sanger sequencing. Data was analysed using SPSS 25.
RESULTS
Of the 39 patients, 15(38.5%) were males and 24(61.5%) were females. The overall median age was 14 (23) years. There were 29 (74.4%) patients with thalassemia family history, and 22(56.4%) had a positive family history of transfusion related to thalassemia, while no patient had a family history of iron therapy. The median haemoglobin A, haemoglobin A2 and haemoglobin F levels were 72.2 (65.2-79.1) %, 26.6 (19.1-34.0) % and 0.9 (-0.8-2.6) %, respectively. After molecular investigation, HbAE mutation was found in 23(59%) patients, while wild type HbAA genotype was found in 16(41%). The heterozygous HbE mutation was present in 23(59%) patients.
CONCLUSIONS
Frequently missed/undiagnosed cases of haemoglobin E that co-elute with haemoglobin A2 in the same high performance liquid chromatography window were detected among those with haemoglobin A2 ≥7%.
Topics: Male; Female; Humans; Adolescent; Hemoglobin E; Hemoglobin A2; Cross-Sectional Studies; Genotype; beta-Thalassemia; Thalassemia; Mutation
PubMed: 38083912
DOI: 10.47391/JPMA.7138 -
Scientific Reports Sep 2023Patients with transfusion-dependent thalassemia (TDT) have an increased risk of osteoporosis and fractures. They also have several potential factors associated with...
Patients with transfusion-dependent thalassemia (TDT) have an increased risk of osteoporosis and fractures. They also have several potential factors associated with sarcopenia. There has been currently no study on sarcopenia and its association with falls and fractures in TDT. This study aims to determine the prevalence of and factors associated with osteoporosis, fragility fractures, and sarcopenia in adults with TDT. A cross-sectional study was conducted at the hematologic clinic at King Chulalongkorn Memorial Hospital, Bangkok, Thailand. Clinical data and laboratory testing were collected. Bone mineral density and morphometric vertebral fracture were assessed. Sarcopenia was defined using the 2014 and 2019 Asian Working Group for Sarcopenia (AWGS) criteria. We included 112 TDT patients aged 35.1 ± 12.5 years. The prevalence of osteoporosis was 38.4%. Fragility fractures were found in 20.5% of patients. Lower BMI (OR 0.29; 95% CI 0.12-0.72, P = 0.007) and hypogonadal state (OR 3.72; 95% CI 1.09-12.74, P = 0.036) were independently associated with osteoporosis. According to the 2014 AWGS criteria, the prevalence of overall sarcopenia and severe sarcopenia was 44.6% and 13.4%, respectively. Severe sarcopenia was strongly associated with fragility fractures (OR 4.59, 95% CI 1.21-17.46, P = 0.025). In conclusion, osteoporosis, fragility fractures, and sarcopenia were prevalent in adults with TDT. Severe sarcopenia was associated with fragility fractures. Early osteoporosis and sarcopenia screening and prevention may reduce fracture risk and its complications in these patients.
Topics: Humans; Sarcopenia; Cross-Sectional Studies; Thailand; Osteoporosis; Fractures, Bone; Bone Density; Thalassemia; Risk Factors
PubMed: 37775530
DOI: 10.1038/s41598-023-43633-6 -
Redox Biology Dec 2023Sickle cell disease (SCD) is a hereditary hematological disease with high morbidity and mortality rates worldwide. Despite being monogenic, SCD patients display a... (Review)
Review
Sickle cell disease (SCD) is a hereditary hematological disease with high morbidity and mortality rates worldwide. Despite being monogenic, SCD patients display a plethora of disease-associated complications including anemia, oxidative stress, sterile inflammation, vaso-occlusive crisis-related pain, and vasculopathy, all of which contribute to multiorgan dysfunction and failure. Over the past decade, numerous small molecule drugs, biologics, and gene-based interventions have been evaluated; however, only four disease-modifying drug therapies are presently FDA approved. Barriers regarding effectiveness, accessibility, affordability, tolerance, and compliance of the current polypharmacy-based disease-management approaches are challenging. As such, there is an unmet pharmacological need for safer, more efficacious, and logistically accessible treatment options for SCD patients. Herein, we evaluate the potential of small molecule nitroalkenes such as nitro-fatty acid (NO-FA) as a therapy for SCD. These agents are electrophilic and exert anti-inflammatory and tissue repair effects through an ability to transiently post-translationally bind to and modify transcription factors, pro-inflammatory enzymes and cell signaling mediators. Preclinical and clinical studies affirm safety of the drug class and a murine model of SCD reveals protection against inflammation, fibrosis, and vascular dysfunction. Despite protective cardiac, renal, pulmonary, and central nervous system effects of nitroalkenes, they have not previously been considered as therapy for SCD. We highlight the pathways targeted by this drug class, which can potentially prevent the end-organ damage associated with SCD and contrast their prospective therapeutic benefits for SCD as opposed to current polypharmacy approaches.
Topics: Humans; Animals; Mice; Anemia, Sickle Cell; Vascular Diseases; Pain; Inflammation
PubMed: 37907055
DOI: 10.1016/j.redox.2023.102941 -
Haematologica Oct 2023Under normal conditions, iron metabolism is carefully regulated to sustain normal cellular functions and the production of hemoglobin in erythroid cells. Perturbation to... (Review)
Review
Under normal conditions, iron metabolism is carefully regulated to sustain normal cellular functions and the production of hemoglobin in erythroid cells. Perturbation to the erythropoiesis-iron metabolism axis can result in iron imbalances and cause anemia or organ toxicity. Various congenital and acquired diseases associated with abnormal red cell production are characterized by aberrant iron absorption. Several recent studies have shown that improvements in red blood cell production also ameliorate iron metabolism and vice versa. Many therapeutics are now under development with the potential to improve a variety of hematologic diseases, from β-thalassemia and iron-refractory iron deficiency anemia to anemia of inflammation and polycythemia vera. This review summarizes selected mechanisms related to red cell production and iron metabolism and describes potential therapeutics and their current uses. We also consider the potential application of the discussed therapeutics on various diseases, alone or in combination. The vast repertoire of drugs under development offers new opportunities to improve the clinical care of patients suffering from congenital or acquired red blood cell disorders with limited or no treatment options.
Topics: Humans; Erythropoiesis; Erythrocytes; Anemia, Iron-Deficiency; Iron; beta-Thalassemia; Hematologic Diseases
PubMed: 37345473
DOI: 10.3324/haematol.2023.283057 -
Medicine May 2024β-Thalassemia is the world's number 1 single-gene genetic disorder and is characterized by suppressed or impaired production of β-pearl protein chains. This results in... (Review)
Review
β-Thalassemia is the world's number 1 single-gene genetic disorder and is characterized by suppressed or impaired production of β-pearl protein chains. This results in intramedullary destruction and premature lysis of red blood cells in peripheral blood. Among them, patients with transfusion-dependent β-thalassemia face the problem of long-term transfusion and iron chelation therapy, which leads to clinical complications and great economic stress. As gene editing technology improves, we are seeing the dawn of a cure for the disease, with its reduction of ineffective erythropoiesis and effective prolongation of survival in critically ill patients. Here, we provide an overview of β-thalassemia distribution and pathophysiology. In addition, we focus on gene therapy and gene editing advances. Nucleic acid endonuclease tools currently available for gene editing fall into 3 categories: zinc finger nucleases, transcription activator-like effector nucleases, and regularly interspaced short palindromic repeats (CRISPR-Cas9) nucleases. This paper reviews the exploratory applications and exploration of emerging therapeutic tools based on 3 classes of nucleic acid endonucleases in the treatment of β-thalassemia diseases.
Topics: beta-Thalassemia; Humans; Gene Editing; Genetic Therapy; CRISPR-Cas Systems; Transcription Activator-Like Effector Nucleases; Zinc Finger Nucleases
PubMed: 38701251
DOI: 10.1097/MD.0000000000038036 -
Revista Da Associacao Medica Brasileira... 2023The objective of this study was to compare the nutritional status and dietary intake of pregnant women with sickle cell disease (SS hemoglobinopathy and SC...
OBJECTIVE
The objective of this study was to compare the nutritional status and dietary intake of pregnant women with sickle cell disease (SS hemoglobinopathy and SC hemoglobinopathy) to healthy controls and report the maternal and perinatal outcomes.
METHODS
This is a prospective, longitudinal cohort study. Pregnant women with a diagnosis of sickle cell disease and control group were recruited in an outpatient clinic of a tertiary care hospital in São Paulo, Brazil. Maternal anthropometric data and dietary intake data were collected at the second and third trimesters.
RESULTS
A total of 49 pregnancies complicated by sickle cell disease were included. Prepregnancy body mass index was significantly lower in the SS hemoglobinopathy group (n=26, median 20.3 kg/m2) than the SC hemoglobinopathy group (n=23, 22.7 kg/m2) or control group (n=33, 23.2 kg/m2, p<0.05). The prepregnancy nutritional status revealed significantly more women classified as underweight in the SS hemoglobinopathy group (15.4%) than in the SC hemoglobinopathy group (4.4%) and control group (1.6%, p=0.009). In the second trimester, maternal protein intake was significantly lower in SS hemoglobinopathy (73.2 g/day) and SC hemoglobinopathy (68.8 g/day) than in the control group (95.7 g/day, p=0.004). In the third trimester, only SS hemoglobinopathy mothers showed dietary intake of protein significantly lower than that of the controls (67.5 g/day vs. 92.8 g/day, p=0.02). Vitamin A and E consumption was also reduced in the third trimester in the SS hemoglobinopathy group (p<0.05).
CONCLUSION
The nutritional status of pregnant women with SS hemoglobinopathy is characterized by a state of undernutrition. The lower protein intake in the second and third trimesters of pregnant women with SS hemoglobinopathy may contribute to this condition. Undernourishment is a serious complication of sickle cell disease, primarily during pregnancy, and it should be addressed during the prenatal period.
Topics: Pregnancy; Female; Humans; Longitudinal Studies; Prospective Studies; Pregnancy Complications, Hematologic; Brazil; Anemia, Sickle Cell; Malnutrition
PubMed: 37878827
DOI: 10.1590/1806-9282.20230967 -
Pediatric Annals Feb 2024
Topics: Humans; Anemia, Sickle Cell
PubMed: 38302119
DOI: 10.3928/19382359-20231205-01