Pharmacological Induction of FOXO3 Is a Potential Treatment for Sickle Cell Disease

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 282-282
Author(s):  
Yankai Zhang ◽  
Jacy R Crosby ◽  
Eric Boerwinkle ◽  
Betty Pace ◽  
Vivien A. Sheehan
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Therapeutic Target ◽  
Off Label Use ◽  
Cell Disease ◽  
Off Label ◽  
Positive Regulator ◽  
Hbf Induction ◽  
Erythroid Maturation ◽  
Label Use

Abstract Sickle cell disease (SCD) affects >100,000 Americans and millions more worldwide. Symptoms and sequelae of SCD can be ameliorated by increasing fetal hemoglobin (HbF, α2γ2) levels. Unfortunately, up to 50% of adult SCD patients treated with hydroxyurea, the only FDA-approved and widely used HbF inducer, do not have a clinically meaningful response to the drug. Additional oral HbF inducing agents, especially those that require less intense laboratory monitoring, are urgently needed. Development of such drugs has been stymied by an incomplete understanding of γ-globin regulation. We hypothesized that natural human genetic variation can be used to identify genes that may be drug targets for HbF induction. To test this hypothesis, we performed whole exome sequencing on 171 pediatric SCD patients to identify variants associated with endogenous HbF levels. Gene-based analysis identified seven unique non-synonymous variations in a Forkhead box O transcription factor, FOXO3, as significantly associated with lower HbF (p=5.6x10-4, β-value of log transformed (ln) HbF= -0.66). Two variants in the α2 subunit of AMPK, a FOXO3 activator, were also associated with reduced HbF (p=1.56x10-4, β-value ln%HbF=-1.5). We then performed functional studies to verify the association between FOXO3 and endogenous HbF levels in an ex vivo model of erythroid differentiation from CD34+ cells isolated from peripheral blood of normal human blood donors. Lentiviral short hairpin RNA (shRNA) knockdown of FOXO3 reduced γ-globin expression from 1 to 0.4, p= 0.0005. While γ-globin expression and protein levels were reduced by FOXO3 knockdown, β-globin levels remained unchanged. These results suggest that FOXO3 is a positive regulator of γ-globin. Morphologic and flow cytometry analysis of primary erythroid culture with and without FOXO3 knockdown indicates that knockdown of FOXO3 delays erythroid maturation, while reducing γ-globin production. We therefore conclude that FOXO3 appears to regulate γ-globin through a specific mechanism rather than through alteration of erythroid maturation kinetics. FOXO3 is a viable therapeutic target for the treatment of individuals with SCD as well as those with quantitative hemoglobinopathies like β-thalassemia, who do not benefit from hydroxyurea due to its delay of erythropoiesis. FOXO3 expression is known to be increased by three drugs, metformin, phenformin, and resveratrol. We found that these drugs also cause FOXO3 to accumulate in the nucleus, where it is active, rather than in the cytoplasm, where FOXO3 is degraded. We have investigated the effects of these agents on FOXO3 and γ-globin expression in K562 cells. Metformin, phenformin and resveratrol increased FOXO3 and γ-globin transcription levels in a dose-dependent manner. We then treated primary erythroid culture cells with a range of metformin doses (20-200µM), with and without a stable dose of 30 µM hydroxyurea. Alone, metformin had a modest effect (1.5 fold) on γ-globin induction at all concentrations. In combination with hydroxyurea, 50 µM metformin increased γ-globin expression 3.7-fold compared to 2.5-fold with hydroxyurea alone when analyzed by RT-qPCR. β-globin levels were unchanged by hydroxyurea or metformin. γ-globin induction persisted through terminal maturation of the culture when measured serially every 5 days. Taken together, our results indicate that not only is FOXO3 is a positive regulator of γ-globin expression, but it is an excellent therapeutic target for HbF induction. Metformin, a well-studied, well tolerated oral agent, will be investigated in combination with hydroxyurea in a phase II trial as an adjunctive agent to increase HbF induction. Disclosures Off Label Use: This presentation will discuss off-label use of metformin as a possible HbF inducing agent..

scholarly journals Comparison of the Safety Profile of Sickle Cell Disease Patients Treated with Hydroxycarbamide in Off-Label Versus in-Label Prescriptions in the Escort-HU Non Interventional, Prospective, Observational Open-Label Cohort Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2497-2497
Author(s):  
Ersi Voskaridou ◽  
Stephan Lobitz ◽  
Uwe Kordes ◽  
Regine Grosse ◽  
Valentine Brousse ◽  
...  
Keyword(s):  
Immune System ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Safety Profile ◽  
Research Funding ◽  
Therapeutic Indication ◽  
Off Label Use ◽  
Cell Disease ◽  
Off Label ◽  
Label Use

Abstract ESCORT-HU (European Sickle Cell Disease (SCD) COhoRT - HydroxyUrea) is a multicenter prospective non interventional study implemented in Europe, following the European Medical Agency's request to collect more information focused on long-term safety profile of hydroxycarbamide (HU) in SCD patients treated with HU. Primary endpoint of the study is to determine the frequency of adverse events (AEs) under HU treatment Secondary endpoints include the efficacy of HU in labeled indications (prevention of vaso-occlusive complications and of acute thoracic syndrome), frequency of hospitalizations due to SCD events and frequency of blood transfusions. Data collection on the reason for HU initiation permitted to identify in-label (in the therapeutic indication of the European marketing authorization, group 1, G1) and off-label (other therapeutic indication, group 2, G2) prescriptions of HU. Frequency of AEs (including not related to SCD and infections) was compared between adults and children, both in G1 and G2, with focus on the following subclasses: blood and lymphatic system disorders, fever, gastrointestinal disorders, infection, nervous system disorders, skin and subcutaneous tissue disorders and others. As of 6th June 2016 (cut-off date), a cohort of 1047 sickle cell patients have been enrolled in 3 European countries (Greece, 11.4%, Germany, 13.4%, and France, 75.2%). Of the 1047 patients, 845 (80.7%) have an in-label prescription (478 adults and 367 children), 170 (16.2%) an off-label prescription (61 adults and 109 children), and 32 reported unknown or no indication (Table 1a). As usually observed in any disease, the off-label use is more frequent in children compared to adults (p=0.01). Main reasons for off-label prescription were anemia (31%) (n=9 in adults and n=44 in children), abnormal Transcranial Doppler (TCD) values/cerebral vasculopathy (15%) (n=2 in adults and n=24 in children) and sickle cell organopathy including renal impairment (15%) (n=14 in adults and n=12 in children) (Table 1b). These three indications follow recommendations issued by European clinicians and are in accordance with the last version of US guidelines (JAMA 2014). Mean HU daily doses at initiation were respectively 18 mg/kg (G1) and 17.3 mg/kg (G2) in children, and 16.2 mg/kg (G1) and 13.5 mg/kg (G2) in adults. Not SCD-related AEs were respectively reported in 25% and 27.6% of patients in G1 and G2 groups (Table 2a). Focusing on the number of not-SCD related AE reported in each group, 355 AE have been reported in 211 patients in G1 and 73 AE have been reported in 47 patients in G2. Within G1 group, more AEs were reported in adults (30.8%) vs. children (17.4%) (p < 0.01) (Table 2b) but not in G2 group (NS) (Table 2c). When compared by AE type in G1, significant differences appeared between children and adults for the following AE subclasses (p < 0.01): infections more frequent in children as usually observed, renal & urinary disorders, immune system disorders more common in adults. Regarding neoplasms benign, immune system disorders, no malignancy has been reported, but mainly cysts (1 ovary, 2 breast), 1 renal tumor and 1 cutaneous lesion (histological types not provided), 1 other (location not reported) (Table 3). All AEs were more frequent in adults except infections. In conclusion, the current ESCORT-HU data confirm the more frequent off-label use of HU in children, a similar frequency of patients reporting not SCD-related AE between the in-label and off-label groups despite a higher number of AE reported in the in-label group, and a significant difference between children and adults in frequency of AEs in the in-label group. Disclosures De Montalembert: Addmedica: Research Funding; Novartis: Research Funding, Speakers Bureau. Ribeil:Bluebirdbio: Consultancy; Addmedica: Research Funding.

HMGB1 Expression in Sickle Cell Disease: A Pro-Inflammatory Cytokine and Potential Therapeutic Target.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3803-3803
Author(s):  
Myra F. Barginear ◽  
Anu G. Chandok ◽  
Cristina Sison ◽  
Lihong Yang ◽  
Daniel R. Budman ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Therapeutic Target ◽  
Vascular Endothelial Cells ◽  
Therapeutic Benefit ◽  
Cell Disease ◽  
Extracellular Milieu ◽  
Hmgb1 Expression ◽  
Attractive Therapeutic Target ◽  
Inflammatory State

Abstract Background: HMGB1 is traditionally known as a DNA binding protein involved in gene transcription. When released into the extracellular milieu, HMGB1 activates vascular endothelial cells and macrophages/monocytes to express proinflammatory cytokines, chemokines, and adhesion molecules. Therefore, HMGB1 may be a good marker for disease activity in Sickle Cell Disease (SCD), a chronic inflammatory state. Methods: After informed consent as per Institutional guidelines, plasma was obtained, frozen, and batch run for HMGB1 levels by ELISA technique in patients with SCD during non-crisis and crisis states. The detection limit of HMGB1 was achieved at concentrations above 1 ng/ml. Each experiment was repeated at least five times to ensure reproducibility. Results: 12 patients enrolled, 6 patients have gone into crisis. HMGB1 levels were measured on consecutive days for 5 five days during a crisis. We established mean HMGB1 expression levels of 32.83 ± 27.13ng/ml during a non-crisis state and 52.57± 15.22 ng/ml during a crisis, respectively (p&lt; .028). In noninflammatory states, HMGB1 is &lt; 5 ng/ml. Conclusion: We have demonstrated, for the first time, a persistent expression of HMGB1 in SCD patients. Although recruitment is on going, this data is consistent with pre-clinical data indicating that HMGB1 may be an important diffusible signal of necrosis-mediated inflammation. Additionally, our laboratory has previously demonstrated therapeutic benefit by neutralization of HMGB1 in sepsis. Thus if confirmed in a larger cohort, anti-HMGB1 therapy to reduce the effects of inflammation may be an attractive therapeutic target in sickle cell disease.

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.

Do Difficulties In Swallowing Medication Impede The Use Of Hydroxyurea In Children?

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2967-2967 ◽  
Author(s):  
Nancy S. Green ◽  
Courtney Thornburg ◽  
Amanda M Brandow ◽  
Mukta Sharma ◽  
ElShadey Bekele ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Medication Use ◽  
Off Label Use ◽  
Cell Disease ◽  
Medication Regimen ◽  
Once Daily ◽  
Off Label ◽  
Liquid Medication ◽  
Swallowing Difficulties ◽  
Do So

Abstract Introduction Barriers to hydroxyurea (HU) use exist for children with sickle cell disease (SCD). Anecdotally, some parents report that their children struggle to swallow HU capsules. We hypothesized that difficulties in swallowing capsules and other forms of daily medication may be a barrier to pediatric HU use. Methods A self-administered survey of parents of children with SCD ages 5-17 years was conducted in pediatric SCD clinics at four different sites (see author affiliations). Parents submitted one survey for each eligible child. We assessed views on their child's medication regimen, including HU; how medications were swallowed; whether swallowing difficulties were perceived as barriers to medication adherence and whether children taking HU had fewer difficulties taking medication. Respondents were grouped by whether children were on HU therapy. Data were analyzed using descriptive statistics, chi square and Fisher exact tests. Results A total of 122 adults completed the survey, with 27-35 surveys obtained from each site. Of survey respondents, 98% were parents and 95% reported being the child's primary caregiver. Half of all children were ages 8-13 years, and 23% were 7 or younger. Groups were evenly divided by whether children were taking HU (n=61 in both groups). There were no significant differences between groups regarding parent or child age, number of children living in the home or choice of the Spanish version of the survey. Parents of children in the group taking HU had a higher level of education (p=0.04). We found 24% of all parents thought that swallowing medications was “hard to do”. Most (85%) parents reported that swallowing difficulties did not preclude daily medication use, with no differences by HU use. All (98%) children could swallow liquid medication, with two thirds reported as able to do so by age 1. In contrast, 76% of children could swallow pills, with 40% able to do so by age 4. No differences by HU use were found in overall ability or age to swallow pills, although more in the HU group could swallow large pills (78.4 vs. 54.2%, p=0.03). No differences between groups were found in ability to swallow capsules. Across all age groups, 26.5% of children could not swallow capsules. Only 20% of all children could swallow capsules by age 4. Of children taking HU, 71.4% used the capsule form. Only 17% of those children open the capsules to mix with a liquid or soft food to aid in swallowing. Few (11%) children in both groups had received training for medication swallowing; most of their parents perceived the training as helpful to their child. While 96% of the children were prescribed medication, children taking HU were more likely than the others to be taking any medication (100 vs. 85%, p=0.001), and twice as likely to take medication on a daily basis (98.4 vs. 51.6%, p=0.001). Parents of children taking HU more often reported that their children took multiple medications (<0.001), including more pills daily (p=0.02). Children on HU had a medication regimen of more than once daily (61.7 vs. 28.6%, p<0.001). Conclusions Based on self-report, the majority of parents of children with SCD did not view medication swallowing as an impediment to daily use of medications, including HU. Children in the HU group reported less difficulty swallowing large pills, but were not different in their ability to ingest capsules, small pills or liquid medication. These data suggest that difficulty swallowing medication is not a barrier to HU use for most children. Nonetheless, a substantial proportion of children ages 5-17 cannot swallow capsules; children under 5 are especially challenged. Therefore, coaching for swallowing to improve HU uptake could be targeted to the modest proportion of children who need assistance. Moreover, a reliable source of liquid HU is still needed for children who cannot swallow capsules. Our findings also suggest that HU use is more likely in families committed to daily medication use and more complex medication schedules, or for children with medical needs requiring therapy beyond once daily HU. Clinicians should continue to educate families about the benefits of HU and address potential impediments such as swallowing HU capsules and complex medication regimens. This study received support from NIH 1R21NR013745 (Green and Smaldone, PIs). Disclosures: Off Label Use: Hydroxyurea for treating children with sickle cell disease is off-label use.

scholarly journals Single Nucleotide Polymorphisms in SAR1A Codon Regions Associated with Hydroxyurea Response in Sickle Cell Disease and Potentially Influenced in Mirnas Binding

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 987-987
Author(s):  
Chutima Kumkhaek ◽  
Christine Kim ◽  
James G. Taylor ◽  
Jianqiong Zhu ◽  
Wulin Aerbajinai ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Single Nucleotide Polymorphisms ◽  
Sickle Cell ◽  
Genetic Variants ◽  
Clinical Heterogeneity ◽  
Nucleotide Polymorphisms ◽  
Cell Disease ◽  
Single Nucleotide ◽  
Coding Regions ◽  
Hbf Induction

Therapeutic induction of fetal hemoglobin (HbF) is one of the most promising approaches to ameliorate the severity of hemoglobinopathies such as β-thalassemia and sickle cell disease (SCD). Among HbF induction agents, hydroxyurea (HU) was approved by FDA to use for the treatment of SCD. However, there is variability in HU response among SCD patients. Individual genetic variants are mostly influenced in differences in pharmacological responsiveness to drug. We previously reported that the small guanosine triphosphate (GTP)-binding protein, secretion-associated and RAS-related (SAR1A) protein was a specific HU-inducible gene. The single nucleotide polymorphisms (SNPs) in SAR1A promoter also contributed to inter-individual differences in regulation of HbF expression and SCD patient responses to HU. Additionally, microRNAs (miRNAs) have been identified as potential key genes that regulate HbF induction and related with the clinical heterogeneity of SCD. Here, we demonstrate that SNPs within SAR1A coding regions are associated with differences in individual responses to HU therapy and potentially influenced in miRNAs binding. In order to determine SNPs in SAR1A coding regions, we sequenced all 8 exons of SAR1A gene in 32 SCD patients. Three (rs56090714, rs3812693, rs56381518)and twenty-four (rs78341510, rs114346554, rs72807054, rs1370644731, rs1491135303, rs1412150420, rs1423653432, rs1480964347, rs1479076497, rs1180306451, rs1482823291, rs1275470720, rs201493587, rs1470556171, rs2394643, rs80028936, rs7919647, rs115340990, rs15801, rs1046747, rs79535872, rs7653, rs1280408553, and rs10586) variants were identified in codon 1 and 8, respectively. Interestingly, codon 2 was found a novel mutation at position 119, C&gt;A. No mutation was detected in codon 3, 4, 5, 6 and 7. Among these SNPs, rs7919647 at codon 8 was highest frequency (96.9%) in SCD patients. Next, we analyzed the association of SNPs and clinical and laboratory profiles using multiple regression. The rs56381518, rs1479076497, rs1180306451, rs1482823291, rs2394643 and rs115340990 showed significant association with total Hb levels after HU treatment in SCD patients. Only rs1180306451 was associated with absolute HbF levels (P= 0.0161). While no SNPs were observed significant association with HbF, F-cell or F-reticulocyte levels. In addition, the potential miRNAs binding to SNPs at 3'UTR regions were determined by using MicroSNiPer. We found miRNAs that may bind to SNPs as shown in Table 1. miR-625-5p, miR-5003-3p, miR-1236-5p, miR4271, miR-345-3p, miR4725-3p, miR-378a-3p, miR-548q and miR-135a-3p were previously identified only in mild-SCD patients. Furthermore, it has been reported that miR-1200 and miR-19b-1-5p were differentially expressed in high HbF levels condition. Our findings highlight the importance of genetic variants in SAR1A codon region that may predict the hydroxyurea response in SCD patients and miRNAs role in clinical heterogeneity of SCD. Disclosures No relevant conflicts of interest to declare.

scholarly journals GDF -15 and Severity Scores in Sickle Cell Disease Patients Attending Nnamdi Azikiwe University Teaching Hospital, Nnewi, Anambra State, Nigeria

2020 ◽  
pp. 31-37
Author(s):  
Chide Okocha ◽  
Patrick Manafa ◽  
Joy Anowi ◽  
Vera Manafa ◽  
Chilota Efobi
Keyword(s):  
Sickle Cell Disease ◽  
Disease Severity ◽  
Sickle Cell ◽  
Teaching Hospital ◽  
Therapeutic Target ◽  
University Teaching ◽  
Cell Disease ◽  
Potential Therapeutic Target ◽  
Anambra State ◽  
Ischaemia Reperfusion

Aim: Granulocyte differentiation factor 15 (GDF15) is a growth factor and biomarker for many disorders where Ischaemia Reperfusion Injury (IRI) is pathophysiologically relevant. Hence the need to evaluate GDF-15 as a biomarker in Sickle Cell Disease (SCD). Study Design: This is a cross sectional study. Place and Duration of Study: Department of Haematology, Nnamdi University Teaching Hospital, Nnewi, Anambra state, Nigeria, between January and December 2018. Methods: Ninety subjects were randomly recruited with haemoglobin (Hb) phenotypes SS (test), AS and AA (controls); numbering 30, 28 and 32 respectively. Disease severity was determined by calculating an objective score. 5 mls of blood was collected and used to determine Full Blood Count (FBC), haemoglobin Phenotype and GDF-15 levels (by Enzyme Linked Immunosorbent assay).  Data collected was analysed using Statistical Package for Social Sciences software version 20 (SPSS Inc., IL, Chicago, USA). P< 0.05 was considered as significant. Results: GDF-15 level was found to be significantly different in the different HB phenotypes p= 0.005 and correlated negatively with sickle cell disease severity (r= -0.307, p= 0.098). The difference between median GDF-15 levels of HBSS subjects with mild and moderate disease was statistically significant at p= 0.01. Conclusion: We hypothesize that GDF-15 may be a potential therapeutic target for intervention against ischaemia/reperfusion induced micro- vascular injury.  Natural GDF-15 mimetics may be useful in taking advantage of this potential therapeutic target.

scholarly journals Genetic diminution of circulating prothrombin ameliorates multiorgan pathologies in sickle cell disease mice

Blood ◽  
2015 ◽  
Vol 126 (15) ◽  
pp. 1844-1855 ◽  
Author(s):  
Paritha I. Arumugam ◽  
Eric S. Mullins ◽  
Shiva Kumar Shanmukhappa ◽  
Brett P. Monia ◽  
Anastacia Loberg ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Therapeutic Target ◽  
Organ Damage ◽  
Disease Outcome ◽  
Cell Disease ◽  
Spontaneous Bleeding ◽  
End Organ Damage ◽  
Key Points ◽  
Novel Therapeutic

Key PointsReduced prothrombin improves survival and ameliorates inflammation and end-organ damage without spontaneous bleeding in sickle cell mice. An individual procoagulant, prothrombin, represents a novel therapeutic target that can improve sickle cell disease outcome.

scholarly journals Elevated ecto-5′-nucleotidase: a missing pathogenic factor and new therapeutic target for sickle cell disease

2018 ◽  
Vol 2 (15) ◽  
pp. 1957-1968 ◽  
Author(s):  
Hong Liu ◽  
Morayo Adebiyi ◽  
Rong Rong Liu ◽  
Anren Song ◽  
Jeanne Manalo ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Disease Severity ◽  
Sickle Cell ◽  
Therapeutic Target ◽  
Therapeutic Strategy ◽  
Specific Inhibition ◽  
Pathogenic Factor ◽  
Cell Disease ◽  
Key Points ◽  
Novel Therapeutic

Key Points CD73-mediated adenosine production contributes to SCD pathogenesis by promoting erythrocyte 2,3-BPG production and sickling. Specific inhibition of CD73 significantly attenuates disease severity of SCD mice and provides a novel therapeutic strategy to treat SCD.

scholarly journals Salubrinal induces fetal hemoglobin expression via the stress-signaling pathway in human sickle erythroid progenitors and sickle cell disease mice

2021 ◽  
Author(s):  
Betty Pace ◽  
Nicole H Lopez ◽  
Biaoru Li ◽  
Chithra Palani ◽  
Umapathy Siddaramappa ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Signaling Pathway ◽  
Sickle Cell ◽  
Fetal Hemoglobin ◽  
Stress Signaling ◽  
Cell Disease ◽  
Erythroid Progenitors ◽  
F Cells ◽  
Hbf Induction ◽  
Stress Signaling Pathway

Sickle cell disease (SCD) is an inherited blood disorder caused by a mutation in the HBB gene leading to hemoglobin S production and polymerization under hypoxia conditions leading to vaso-occlusion, chronic hemolysis, and progressive organ damage. This disease affects ~100,000 people in the United States and millions worldwide. An effective therapy for SCD is fetal hemoglobin (HbF) induction by pharmacologic agents such as hydroxyurea, the only Food and Drug Administration-approved drug for this purpose. Therefore, the goal of our study was to determine whether salubrinal (SAL), a selective protein phosphatase 1 inhibitor, induces HbF expression through the stress-signaling pathway by activation of p-eIF2α and ATF4 trans-activation in the γ-globin gene promoter. Sickle erythroid progenitors treated with 24µM SAL increased F-cells levels 1.4-fold (p=0.021) and produced an 80% decrease in reactive oxygen species. Western blot analysis showed SAL enhanced HbF protein by 1.6-fold (p=0.0441), along with dose-dependent increases of p-eIF2α and ATF4 levels. Subsequent treatment of SCD mice by a single intraperitoneal injection of SAL (5mg/kg) produced peak plasma concentrations at 6 hours. Chronic treatments of SCD mice with SAL mediated a 2.3-fold increase in F-cells (p=0.0013) and decreased sickle erythrocytes supporting in vivo HbF induction.

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