scholarly journals New Therapeutic Options: Alternates to Gene Therapy for Treating Hemoglobinopathies

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. SCI-49-SCI-49
Author(s):  
Lucia De Franceschi
Keyword(s):  
Gene Therapy ◽  
Sickle Cell ◽  
Iron Chelation ◽  
Organ Damage ◽  
Therapeutic Strategies ◽  
Therapeutic Options ◽  
Red Cell ◽  
Novel Therapies ◽  
Ineffective Erythropoiesis ◽  
Hematopoietic Stem

Hemoglobinopathies are chronic, invalidating globally distributed hereditary red cell disorders, which impact patient survival and quality of life. Sickle cell disease (SCD) and β-thalassemias are the more frequent hemoglobinopathies worldwide. In both SCD and β-thalassemias, novel therapeutic strategies might be divided into (1) pathophysiology related therapies and (2) innovative curative therapeuties such as hematopoietic stem cell transplantation and gene therapy, the latter discussed in another presentation in this session. In the last two decades, studies have highlighted the biocomplexity of SCD and β-thalassemias and the need for the development of new therapeutic options targeting one or more of the mechanisms involved in their pathogenesis. In SCD, the pathophysiology related novel therapies might be divided into: (i)Molecules targeting sickling and red cell dehydration; (ii) Molecules targeting SCD vasculopathy and sickle cell-endothelial adhesive events; (iii) Molecules modulating SCD related oxidative stress. Since inflammatory vasculopathy is a key factor in SCD related organ damage, major efforts have been made to develop agents that interfere with SCD vasculopathy and adhesion events, involving sickle red cells, neutrophils and endothelial interplay. β-thalassemic syndromes are characterized by ineffective erythropoiesis, which plays a crucial role in anemia and in the development of extramedullar erythropoiesis. In β-thalassemic syndromes, pathophysiology related novel therapies might be divided into: (i) Agents reducing the ineffective erythropoiesis such the TRAP ligands, targeting the GDF11 pathway (sotatercept or luspatercept); (ii) Agents affecting Jak2 activation to reduce splenomegaly in β-thalassemia and (iii) Agents modulating hepcidin - erythropoiesis axis such as minihepcidins. The main goal of these molecules is to ameliorate the ineffective erythropoiesis resulting in increased hemoglobin levels with reduction of transfusion requirement, iron overload, and facilitating iron chelation therapy. This review highlights new therapeutic strategies in SCD and β-thalassemia and discusses future development, research implications, and possible directions toward future clinical trials. Disclosures De Franceschi: F. Hoffmann-La Roche Ltd, Basel, Switzerland: Research Funding.

scholarly journals NEW THERAPEUTIC OPTIONS FOR THE TREATMENT OF SICKLE CELL DISEASE

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Alessandro Matte ◽  
Filippo Mazzi ◽  
Enrica Federti ◽  
Oliviero Olivieri ◽  
Lucia De Franceschi
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Therapeutic Strategies ◽  
Therapeutic Options ◽  
High Morbidity ◽  
Novel Therapies ◽  
Cell Disease ◽  
Hematopoietic Stem ◽  
Positive Effects ◽  
Cell Dehydration

Sickle cell disease (SCD; ORPHA232; OMIM # 603903) is a chronic and invalidating disorder distributed worldwide, with high morbidity and mortality.  Given the disease complexity and the multiplicity of pathophysiological targets, development of new therapeutic options is critical, despite the positive effects of hydroxyurea (HU), for many years the only approved drug for SCD. New therapeutic strategies might be divided into (1) pathophysiology-related novel therapies and (2) innovations in curative therapeutic options such as hematopoietic stem cell transplantation and gene therapy. The pathophysiology related novel therapies are: a) Agents which reduce sickling or prevent sickle red cell dehydration; b) Agents targeting SCD vasculopathy and sickle cell-endothelial adhesive events; c) Anti-oxidant agents. This review highlights new therapeutic strategies in SCD and discusses future developments, research implications, and possible innovative clinical trials.  

Sickle Cell Disease Hematopoietic Stem Cell gene therapy with globin gene addition is promising

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Gene Therapy ◽  
Stem Cell ◽  
Sickle Cell Disease ◽  
Hematopoietic Stem Cell ◽  
Sickle Cell ◽  
Globin Gene ◽  
Autologous Transplantation ◽  
Gene Repair ◽  
Cell Disease ◽  
Hematopoietic Stem

Autologous transplantation of gene-modified HSCs might be used to treat Sickle Cell Disease (SCD) once and for all. Hematopoietic Stem Cell (HSC) gene therapy with lentiviral-globin gene addition was optimized by HSC collection, vector constructs, lentiviral transduction, and conditioning in the current gene therapy experiment for SCD, resulting in higher gene marking and phenotypic correction. Further advancements over the next decade should allow for a widely approved gene-addition therapy. Long-term engraftment is crucial for gene-corrected CD34+ HSCs, which might be addressed in the coming years, and gene repair of the SCD mutation in the-globin gene can be achieved in vitro using genome editing in CD34+ cells. Because of breakthroughs in efficacy, safety, and delivery strategies, in vivo gene addition and gene correction in BM HSCs is advancing. Overall, further research is needed, but HSC-targeted gene addition/gene editing therapy is a promising SCD therapy with curative potential that might be widely available soon.

scholarly journals Reconstruction of Sickle Cell Disease with Circulating Sickling Red Blood Cells in Novel Humanized Cytokines and Liver Mistrg Mice

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 29-30
Author(s):  
Yuanbin Song ◽  
Rana Gbyli ◽  
Liang Shan ◽  
Wei Liu ◽  
Yimeng Gao ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Mouse Model ◽  
Red Blood Cells ◽  
Sickle Cell ◽  
Blood Cells ◽  
Red Cell ◽  
Cell Disease ◽  
Ineffective Erythropoiesis ◽  
Cd34 Cells

In vivo models of human erythropoiesis with generation of circulating mature human red blood cells (huRBC) have remained elusive, limiting studies of primary human red cell disorders. In our prior study, we have generated the first combined cytokine-liver humanized immunodeficient mouse model (huHepMISTRG-Fah) with fully mature, circulating huRBC when engrafted with human CD34+ hematopoietic stem and progenitor cells (HSPCs)1. Here we present for the first time a humanized mouse model of human sickle cell disease (SCD) which replicates the hallmark pathophysiologic finding of vaso-occlusion in mice engrafted with primary patient-derived SCD HSPCs. SCD is an inherited blood disorder caused by a single point mutation in the beta-globin gene. Murine models of SCD exclusively express human globins in mouse red blood cells in the background of murine globin knockouts2 which exclusively contain murine erythropoiesis and red cells and thus fail to capture the heterogeneity encountered in patients. To determine whether enhanced erythropoiesis and most importantly circulating huRBC in engrafted huHepMISTRG-Fah mice would be sufficient to replicate the pathophysiology of SCD, we engrafted it with adult SCD BM CD34+ cells as well as age-matched control BM CD34+ cells. Overall huCD45+ and erythroid engraftment in BM (Fig. a, b) and PB (Fig. c, d) were similar between control or SCD. Using multispectral imaging flow cytometry, we observed sickling huRBCs (7-11 sickling huRBCs/ 100 huRBCs) in the PB of SCD (Fig. e) but not in control CD34+ (Fig. f) engrafted mice. To determine whether circulating huRBC would result in vaso-occlusion and associated findings in SCD engrafted huHepMISTRG-Fah mice, we evaluated histological sections of lung, liver, spleen, and kidney from control and SCD CD34+ engrafted mice. SCD CD34+ engrafted mice lungs showed an increase in alveolar macrophages (arrowheads) associated with alveolar hemorrhage and thrombosis (arrows) but not observed control engrafted mice (Fig. g). Spleens of SCD engrafted mice showed erythroid precursor expansion, sickled erythrocytes in the sinusoids (arrowheads), and vascular occlusion and thrombosis (arrows) (Fig. h). Liver architecture was disrupted in SCD engrafted mice with RBCs in sinusoids and microvascular thromboses (Fig. i). Congestion of capillary loops and peritubular capillaries and glomeruli engorged with sickled RBCs was evident in kidneys (Fig. j) of SCD but not control CD34+ engrafted mice. SCD is characterized by ineffective erythropoiesis due to structural abnormalities in erythroid precursors3. As a functional structural unit, erythroblastic islands (EBIs) represent a specialized niche for erythropoiesis, where a central macrophage is surrounded by developing erythroblasts of varying differentiation states4. In our study, both SCD (Fig. k) and control (Fig. l) CD34+ engrafted mice exhibited EBIs with huCD169+ huCD14+ central macrophages surrounded by varying stages of huCD235a+ erythroid progenitors, including enucleated huRBCs (arrows). This implies that huHepMISTRG-Fah mice have the capability to generate human EBIs in vivo and thus represent a valuable tool to not only study the effects of mature RBC but also to elucidate mechanisms of ineffective erythropoiesis in SCD and other red cell disorders. In conclusion, we successfully engrafted adult SCD patient BM derived CD34+ cells in huHepMISTRG-Fah mice and detected circulating, sickling huRBCs in the mouse PB. We observed pathological changes in the lung, spleen, liver and kidney, which are comparable to what is seen in the established SCD mouse models and in patients. In addition, huHepMISTRG-Fah mice offer the opportunity to study the role of the central macrophage in human erythropoiesis in health and disease in an immunologically advantageous context. This novel mouse model could therefore serve to open novel avenues for therapeutic advances in SCD. Reference 1. Song Y, Shan L, Gybli R, et. al. In Vivo reconstruction of Human Erythropoiesis with Circulating Mature Human RBCs in Humanized Liver Mistrg Mice. Blood. 2019;134:338. 2. Ryan TM, Ciavatta DJ, Townes TM. Knockout-transgenic mouse model of sickle cell disease. Science. 1997;278(5339):873-876. 3. Blouin MJ, De Paepe ME, Trudel M. Altered hematopoiesis in murine sickle cell disease. Blood. 1999;94(4):1451-1459. 4. Manwani D, Bieker JJ. The erythroblastic island. Curr Top Dev Biol. 2008;82:23-53. Disclosures Xu: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Flavell:Zai labs: Consultancy; GSK: Consultancy.

scholarly journals Potential role of LSD1 inhibitors in the treatment of sickle cell disease: a review of preclinical animal model data

2018 ◽  
Vol 315 (4) ◽  
pp. R840-R847 ◽  
Author(s):  
Angela Rivers ◽  
Ramasamy Jagadeeswaran ◽  
Donald Lavelle
Keyword(s):  
Reactive Oxygen Species ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Globin Gene ◽  
Reactive Oxygen ◽  
Organ Damage ◽  
The United States ◽  
Oxygen Species ◽  
Cell Disease ◽  
Hematopoietic Stem

Sickle cell disease (SCD) is caused by a mutation of the β-globin gene (Ingram VM. Nature 180: 326–328, 1957), which triggers the polymerization of deoxygenated sickle hemoglobin (HbS). Approximately 100,000 SCD patients in the United States and millions worldwide (Piel FB, et al. PLoS Med 10: e1001484, 2013) suffer from chronic hemolytic anemia, painful crises, multisystem organ damage, and reduced life expectancy (Rees DC, et al. Lancet 376: 2018–2031, 2010; Serjeant GR. Cold Spring Harb Perspect Med 3: a011783, 2013). Hematopoietic stem cell transplantation can be curative, but the majority of patients do not have a suitable donor (Talano JA, Cairo MS. Eur J Haematol 94: 391–399, 2015). Advanced gene-editing technologies also offer the possibility of a cure (Goodman MA, Malik P. Ther Adv Hematol 7: 302–315, 2016; Lettre G, Bauer DE. Lancet 387: 2554–2564, 2016), but the likelihood that these strategies can be mobilized to treat the large numbers of patients residing in developing countries is remote. A pharmacological treatment to increase fetal hemoglobin (HbF) as a therapy for SCD has been a long-sought goal, because increased levels of HbF (α2γ2) inhibit the polymerization of HbS (Poillin WN, et al. Proc Natl Acad Sci USA 90: 5039–5043, 1993; Sunshine HR, et al. J Mol Biol 133: 435–467, 1979) and are associated with reduced symptoms and increased lifespan of SCD patients (Platt OS, et al. N Engl J Med 330: 1639–1644, 1994; Platt OS, et al. N Engl J Med 325: 11–16, 1991). Only two drugs, hydroxyurea and l-glutamine, are approved by the US Food and Drug Administration for treatment of SCD. Hydroxyurea is ineffective at HbF induction in ~50% of patients (Charache S, et al. N Engl J Med 332: 1317–1322, 1995). While polymerization of HbS has been traditionally considered the driving force in the hemolysis of SCD, the excessive reactive oxygen species generated from red blood cells, with further amplification by intravascular hemolysis, also are a major contributor to SCD pathology. This review highlights a new class of drugs, lysine-specific demethylase (LSD1) inhibitors, that induce HbF and reduce reactive oxygen species.

scholarly journals New therapeutic targets in transfusion-dependent and -independent thalassemia

Hematology ◽  
2017 ◽  
Vol 2017 (1) ◽  
pp. 278-283 ◽  
Author(s):  
M. Domenica Cappellini ◽  
Irene Motta
Keyword(s):  
Iron Overload ◽  
Ex Vivo ◽  
Wide Spectrum ◽  
Disease Process ◽  
Iron Chelation ◽  
Current Treatment ◽  
Compound Heterozygous ◽  
Ineffective Erythropoiesis ◽  
Hematopoietic Stem ◽  
Hemoglobin E

Abstract β-Thalassemias are characterized by reduced production of β-globin chain, resulting in α/β-chain unbalance and precipitation of α-globin–heme complexes and determining ineffective erythropoiesis. Ineffective erythropoiesis, chronic hemolytic anemia, and compensatory hematopoietic expansion are the disease hallmarks, and they are related to the severity of the chain unbalance. Several clinical forms of β-thalassemia, including the coinheritance of β-thalassemia with hemoglobin E resulting in hemoglobin E/β-thalassemia, have been described. Clinically, β-thalassemias can be classified as transfusion-dependent thalassemia (TDT) and non–transfusion-dependent thalassemia (NTDT) according to the severity of the phenotype, which is caused by a wide spectrum of mutations in a homozygous or compound heterozygous state. Current treatment of TDT consists of regular transfusions that lead to iron overload, requiring iron chelation to prevent iron-related organ toxicity. NTDT patients do not require transfusions or only occasionally require them; however, they develop iron overload as well because of increased intestinal iron absorption caused by chronic anemia. Hematopoietic stem cell allogenic transplant is the only approved cure for β-thalassemia; however, it is still limited by clinical conditions and the availability of matched donors as well as by potential graft-versus-host disease (GVHD). Gene therapy could avoid the GVHD risk, although hematopoietic stem cells must be genetically modified ex vivo. Epigenetic manipulation and genomic editing are novel experimental approaches. An increased understanding of the pathophysiology that controls the disease process prompted us to explore alternative therapeutic approaches that address the underlying chain unbalance, ineffective erythropoiesis, and iron dysregulation. Molecules, such as JAK2 inhibitors and the activin-receptor ligand trap that target ineffective erythropoiesis, are already in clinical trials with promising results. Other agents aimed to generate iron-restricted erythropoiesis are also under experimental evaluation.

Hydroxyurea Therapy Requires HbF Induction for Clinical Benefit in a Sickle Cell Mouse Model.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 817-817
Author(s):  
Jeffrey D. Lebensburger ◽  
Tamara I Pestina ◽  
Kelli Boyd ◽  
Russell E. Ware ◽  
Derek Persons
Keyword(s):  
Gene Therapy ◽  
Sickle Cell ◽  
Pediatric Patients ◽  
Organ Damage ◽  
Off Label Use ◽  
Cell Disease ◽  
Off Label ◽  
Cell Gene ◽  
Stem Cell Gene ◽  
Hydroxyurea Therapy

Abstract Abstract 817 PURPOSE: To evaluate whether there are clinical benefits from chronic hydroxyurea administration that are independent of HbF induction using a murine SCD model in which fetal hemoglobin (HbF) cannot be induced. METHODS: Cohorts of sex- and aged-matched SCD mice were generated by transplanting lethally irradiated C57/BL6 mice with bone marrow from BERK mice. Only mice fully engrafted with SCD hematopoiesis were used for study. Transplanted SCD mice were injected by intraperitoneal route five days per week. SCD mice with high levels of HbF were generated by stem cell gene transfer using a gamma-globin lentiviral vector followed by transplantation. RESULTS: We identified a dose of hydroxyurea (50 mg/kg) that would lead to a stable, well-tolerated reduction in neutrophil count, much like what is done to titrate dosage in human patients with SCD. Hydroxyurea dosed at 25 mg/kg produced no difference in blood counts compared to control mice, while 75 mg/kg and 100 mg/kg both produced critical pancytopenia. As expected, cellulose acetate gel electrophoresis and HPLC analysis showed that HbF was undetectable in both hydroxyurea-treated and saline-treated mice. Based on this dose-finding data, we treated SCD mice with 50 mg/kg hydroxyurea (n=20) and saline (n=13) five days/week for 20 weeks in order to determine whether chronic hydroxyurea therapy could improve both the anemia and organ damage of SCD. Blood counts obtained after 10 weeks again demonstrated a reduction in white blood cells (26.1 vs. 31.2 ×109/L, p<0.005), absolute neutrophil counts (2.9 vs. 4.6 ×109/L, p<0.005), platelets (780 vs 870 × 109/L, p<0.05), without improvement in the anemia (6.7 vs 6.6 g/dL). Consistent with this data, the serum LDH and total bilirubin values remained elevated, similar to control mice, suggesting no improvement in the rate of hemolysis. Necropsy and pathologic analyses of major organs were performed on six mice from each group after 18-20 weeks of hydroxyurea therapy. Hydroxyurea-treated mice showed no improvement in the severe, multi-organ damage, compared to saline-treated, control mice. In contrast, six SCD mice with high levels of HbF resulting from stem cell gene transfer but not treated with hydroxyurea had a significant correction of their anemia (10.8 g/dL) along with a reduction in both total white blood cell (11.7 ×109/L) and absolute neutrophil counts (2.6 × 109/L). The reduction in the neutrophil count secondary to the correction of the anemia by gene therapy was similar to the levels demonstrated with hydroxyurea administration (hydroxyurea ANC 2.9 × 109/L vs. gene therapy ANC 2.6 × 109/L). Importantly, the SCD mice with high HbF demonstrated no significant organ damage. CONCLUSIONS: Despite causing a significant reduction in the leukocytosis and thrombocytosis, hydroxyurea treatment did not improve the severe anemia and multi-organ disease pathology in SCD mice. In contrast, SCD mice with high levels of HbF resulting from stem cell gene therapy showed resolution of both the anemia and organ pathology. These data suggest that induction of HbF is a necessary and major contributor to the beneficial effects of hydroxyurea in SCD. Disclosures: Off Label Use: Hydroxyurea use in pediatric patients sickle cell disease. This abstract does not discuss the off label use of Hydroxyurea in pediatric patients with sickle cell disease. However, discussion of this abstract would likely result in referencing the off label use of hydroxyurea in pediatric patients with sickle cell disease.

Estimating Iron Burden in Simple Vs. Modified Manual Exchange Transfusions in Pediatric Sickle Cell Patients on Chronic Transfusions

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4850-4850
Author(s):  
Mansi Lalwani ◽  
Mary DeBarr ◽  
Ann O'Riordan Mary ◽  
Connie M Piccone ◽  
Brian W Berman
Keyword(s):  
Iron Overload ◽  
Sickle Cell ◽  
Exchange Transfusion ◽  
Chelation Therapy ◽  
Iron Chelation ◽  
Red Cell ◽  
Cell Disease ◽  
Transfusion Therapy ◽  
Packed Red Blood Cells ◽  
Transfusion Protocol

Abstract Abstract 4850 Introduction: Nearly 100,000 Americans are affected by sickle cell disease (SCD), making it one of the most prevalent genetic disorders in the United States. Individuals with SCD exhibit significant morbidity and mortality related to chronic hemolysis, vasculopathy, and vascular occlusion by red cell sickling. Currently, red cell transfusions are a primary therapy for some of the acute and chronic complications of SCD, including prevention and treatment of stroke. The benefits of transfusion therapy are well known; however, transfusional iron overload is an inevitable consequence. Excess iron in the circulation leads to the formation of reactive oxygen species which ultimately causes end-organ damage. It is well established that adult SCD patients with significant iron overload have a higher mortality. As a result, exchange transfusion protocols are utilized to try to decrease overall iron overload. In our center, a modified manual exchange (MME) protocol is used which involves therapeutic phlebotomy of approximately 5–7.5ml/kg followed by the infusion of 15–20ml/kg packed red blood cells. MME is performed in the outpatient setting every 4–6 weeks with a goal hemoglobin S of less than 30%. Objective: The primary objective of our study was to describe the benefits of a MME protocol compared with a simple transfusion protocol in patients experiencing both. The effects of MME versus simple tranfusion on systemic iron overload were evaluated using serum ferritin levels, net transfusion volume, and need for iron chelation therapy. Study Design/Methods: A retrospective chart review was performed on patients with SCD (type SS) less than 18 years of age who were on chronic transfusions and transitioned from a simple to a MME protocol. All patients included were on chronic transfusions for primary/secondary stroke prevention. Exclusion criteria included all patients on automated exchange transfusion protocols and those patients who started iron chelation therapy after January 1, 2008. Demographic as well as clinical and laboratory data were collected on each patient. A simple transfusion was defined as 20ml/kg packed red blood cells transfused every 4–6 weeks. The MME protocol was defined as above. Iron overload was assessed using indicators including net volume of blood transfused, serum ferritin, and the need for iron chelation during both time periods, and differences were calculated. The Wilcoxon signed rank test was used for the change in amount of blood transfused. Slopes of ferritin levels over time were estimated for each transfusion protocol separately using mixed model methods. The need for chelation therapy was tabulated for each patient. Results: A total of six patients were included in the study, 4 boys and 2 girls. Ages ranged from 6–14 years. Four patients had been on chronic transfusions for more than 2 years prior to the start of our study. The mean net volume transfused during simple transfusion and MME was 400ml and 290ml, respectively (p=0.03). The slope of ferritin rise was 0.18 (CI: 0.11, 0.84) for MME and 1.37 (CI: 0.56, 2.17) for simple transfusion. One patient was taken off chelation therapy completely after transitioning to MME and another patient was maintained on low-dose chelation while on MME. Conclusions: MME appears to reduce the amount of blood transfused, slow the rise of ferritin, and potentially reduce the need for additional medication. MME may provide a safe and cost effective approach for delaying or preventing iron overload in patients with sickle cell disease who require long term transfusion therapy. Disclosures: No relevant conflicts of interest to declare.

Using Social Media to Assess Patient and Family Perceptions of Bone Marrow Transplant, Gene Therapy and Other Potentially Curative Treatments for Sickle Cell Disease (SCD)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5921-5921
Author(s):  
Charles Jonassaint ◽  
Aisha L Walker ◽  
Rosta Farzan ◽  
Laura M. De Castro ◽  
Tosin Ola ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Social Media ◽  
Bone Marrow ◽  
Clinical Trials ◽  
Sickle Cell ◽  
Patient Perceptions ◽  
Novel Therapies ◽  
Cell Disease ◽  
Social Media Data ◽  
Media Data

Abstract Introduction: Sickle cell disease (SCD) is an inherited blood disorder associated with frequent pain, end-organ damage and early mortality. The daily management of SCD is often a burden to patients and their families and imposes significant costs on the healthcare system. Recent medical advancements present potential curative treatments for SCD. The efficacy and outcomes for bone marrow transplantation (BMT) is steadily improving and new interventions such as gene therapy (GT) are being actively pursued. The success of these treatments, however, is dependent on patient's acceptance of novel therapies and willingness to enroll in clinical trials. Effective dissemination of new therapies requires understanding patient perceptions and ensuring they are appropriately informed and educated on the benefits and risks of each therapy. There is limited data, however, on patient attitudes toward novel therapies or effective methods for improving patient education and perceptions. A significant segment of the SCD community uses social media to seek health information or share their own views. User-generated data from these social media sites is a rich source of information for understanding patient-level barriers and facilitators to effective health care. Social media data may be more effective than traditional qualitative research approaches for identifying patient and family member perceptions of SCD-related therapies. Study Objective: In the current study we examined user-generated data obtained from Facebook to understand their perceptions and primary concerns regarding curative therapies (e.g. BMT, GT) and treatments currently in the clinical trial stage. Methods: We extracted 4 years (2012-2016) of data from the two SCD Facebook groups with the highest membership: Sickle Cell Warriors and Sickle Cell Unite. For each post we retrieved: number of likes and comments, and the message itself. We filtered posts using search terms for BMT, GT and drugs in clinical trials. We employed linguistic inquiry word count (LIWC) text analysis tools to extract language features from these messages; particularly, to understand psychological construct used in each messages, including affective, cognitive, and social processes. Each message was coded as having a positive, negative or neutral valence. To understand patient perceptions and knowledge regarding curative treatments and trial drugs, we will perform a qualitative analysis of the data using deductive codes according to published studies identified barriers and facilitators and inductive coding to identify previously unknown themes related to patient perceptions and knowledge. Results: A total of 39,817 (8693 Warriors, 31124 Unite) original posts were extracted from the two SCD Facebook sites; 485 (1.2%) of these posts were BMT, GT or trial-drug related. There were 3291 comments to these post. On average, each posts received 6.7 (SD=11.2) comments and 17.6 (SD=44.4) likes. Posts related to treatments generated similar attention (i.e. comments and likes) to other types of posts on these Facebook sites. The LIWC analyses showed a more positive than negative sentiment expressed in the treatment posts; 72%-75% of posts include positive terms while 46%-48% of posts include negative terms. Qualitative analysis of the post content to reveal themes and specific topics discussed is forthcoming. Conclusions: To our knowledge, this is the first study to use social media data to gather and analyze patient perception and knowledge regarding curative therapies and drug trials in SCD. This has implications for understanding how to improve patient perceptions and increase patient education which are keys for fostering patient participation in treatments and trials of novel treatments Disclosures No relevant conflicts of interest to declare.

scholarly journals Elimination of the fibrinogen integrin αMβ2-binding motif improves renal pathology in mice with sickle cell anemia

2019 ◽  
Vol 3 (9) ◽  
pp. 1519-1532 ◽  
Author(s):  
Md Nasimuzzaman ◽  
Paritha I. Arumugam ◽  
Eric S. Mullins ◽  
Jeanne M. James ◽  
Katherine VandenHeuvel ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Globin Gene ◽  
White Blood Cells ◽  
Coagulation Factor ◽  
Vascular Occlusion ◽  
Organ Damage ◽  
Binding Motif ◽  
Mutant Form ◽  
Hematopoietic Stem

Abstract Sickle cell anemia (SCA) is caused by a point mutation in the β-globin gene that leads to devastating downstream consequences including chronic hemolytic anemia, episodic vascular occlusion, and cumulative organ damage resulting in death. SCA patients show coagulation activation and inflammation even in the absence of vascular occlusion. The coagulation factor fibrinogen is not only central to hemostasis but also plays important roles in pathologic inflammatory processes, in part by engaging neutrophils/macrophages through the αMβ2 integrin receptor. To determine whether fibrin(ogen)-mediated inflammation is a driver of SCA-associated pathologies, hematopoietic stem cells from Berkeley sickle mice were transplanted into homozygous Fibγ390-396A mice that express normal levels of a mutant form of fibrin(ogen) that does not engage αMβ2. Fibγ390-396A mice with SCA displayed an impressive reduction of reactive oxygen species (ROS) in white blood cells (WBCs), decreased circulating inflammatory cytokines/chemokines, and significantly improved SCA-associated glomerular pathology highlighted by reduced glomerulosclerosis, inflammatory cell infiltration, ischemic lesions, mesangial thickening, mesangial hypercellularity, and glomerular enlargement. In addition, Fibγ390-396A mice with SCA had improved glomerular protective responses and podocyte/mesangial transcriptional signatures that resulted in reduced albuminuria. Interestingly, the fibrinogen γ390-396A mutation had a negligible effect on cardiac, lung, and liver functions and pathologies in the context of SCA over a year-long observation period. Taken together, our data support that fibrinogen significantly contributes to WBC-driven inflammation and ROS production, which is a key driver of SCA-associated glomerulopathy, and may represent a novel therapeutic target against irreversible kidney damage in SCA.

Recent Progress in Gene Therapy and Other Targeted Therapeutic Approaches for Beta Thalassemia

2019 ◽  
Vol 20 (16) ◽  
pp. 1603-1623 ◽  
Author(s):  
Eman M. Hamed ◽  
Mohamed Hussein Meabed ◽  
Usama Farghaly Aly ◽  
Raghda R.S. Hussein
Keyword(s):  
Gene Therapy ◽  
Cell Transplantation ◽  
B Cell Lymphoma ◽  
Thalassemia Major ◽  
Phase Iii ◽  
Beta Thalassemia ◽  
Ineffective Erythropoiesis ◽  
Hematopoietic Stem ◽  
Beta Thalassemia Major ◽  
Autologous Cell Transplantation

Beta-thalassemia is a genetic disorder characterized by the impaired synthesis of the betaglobin chain of adult hemoglobin. The disorder has a complex pathophysiology that affects multiple organ systems. The main complications of beta thalassemia are ineffective erythropoiesis, chronic hemolytic anemia and hemosiderosis-induced organ dysfunction. Regular blood transfusions are the main therapy for beta thalassemia major; however, this treatment can cause cardiac and hepatic hemosiderosis – the most common cause of death in these patients. This review focuses on unique future therapeutic interventions for thalassemia that reverse splenomegaly, reduce transfusion frequency, decrease iron toxicity in organs, and correct chronic anemia. The targeted effective protocols include hemoglobin fetal inducers, ineffective erythropoiesis correctors, antioxidants, vitamins, and natural products. Resveratrol is a new herbal therapeutic approach which serves as fetal Hb inducer in beta thalassemia. Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for beta thalassemia major and is preferred over iron chelation and blood transfusion for ensuring long life in these patients. Meanwhile, several molecular therapies, such as ActRIIB/IgG1 Fc recombinant protein, have emerged to address complications of beta thalassemia or the adverse effects of current drugs. Regarding gene correction strategies, a phase III trial called HGB-207 (Northstar-2; NCT02906202) is evaluating the efficacy and safety of autologous cell transplantation with LentiGlobin. Advanced gene-editing approaches aim to cut DNA at a targeted site and convert HbF to HbA during infancy, such as the suppression of BCL11A (B cell lymphoma 11A), HPFH (hereditary persistence of fetal hemoglobin) and zinc-finger nucleases. Gene therapy is progressing rapidly, with multiple clinical trials being conducted in many countries and the promise of commercial products to be available in the near future.

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