scholarly journals GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease

2016 ◽  
Vol 174 (4) ◽  
pp. 499-500 ◽  
Author(s):  
Frank A. Ferrone
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Murine Model ◽  
Half Life ◽  
Oxygen Affinity ◽  
Cell Disease

GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease

2016 ◽  
Vol 175 (1) ◽  
pp. 141-153 ◽  
Author(s):  
Donna Oksenberg ◽  
Kobina Dufu ◽  
Mira P. Patel ◽  
Chihyuan Chuang ◽  
Zhe Li ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Murine Model ◽  
Half Life ◽  
Oxygen Affinity ◽  
Cell Disease

Modified Actriib-Fc Fusion Protein (ACE-536) Mitigates Sickling and Red Cell Pathology in a Murine Model of Sickle Cell Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4055-4055
Author(s):  
Rajasekhar NVS Suragani ◽  
Robert Li ◽  
Sharon M Cawley ◽  
R. Scott Pearsall ◽  
Ravindra Kumar
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Murine Model ◽  
Half Life ◽  
Annexin V ◽  
Red Cell ◽  
Oxygen Species ◽  
Cell Disease ◽  
Employment Equity ◽  
Equity Ownership

Abstract Sickle cell disease (SCD) is a debilitating hereditary disorder caused by a single point mutation in the β-globin gene resulting in the production of sickle hemoglobin variant (HbS). In the deoxygenated state, HbS is labile and undergoes auto-oxidation and polymerizes to generate rigid and irreversibly sickled erythrocytes. The pathophysiology of SCD include increased red cell hemolysis, reactive oxygen species and phosphatidylserine (PS) exposure on RBC membranes which leads to a very short red cell half-life, increased reticulocytosis and splenomegaly. Sickled RBCs show enhanced adherence to activated endothelium causing chronic inflammation leading to frequent and acute painful vaso-occlusive crises in SCD patients. Hydroxyurea (HU) augments fetal hemoglobin production, decreases irreversible sickle cells and painful events, and is the only approved therapy for SCD patients. However, recent studies have shown dose limiting myelosupression with HU treatment. Approximately one-third of patients do not respond to HU therapy thereby highlighting the need for alternative treatment strategies. ACE-536 is a modified type IIB activin receptor-Fc fusion protein (ACE-536)1 which functions as a ligand trap for certain members of the TGFβ superfamily. In a murine model of β-thalassemia, RAP-536 (murine ortholog of ACE-536) treatment reduced hemichromes on RBC membranes, decreased reactive oxygen species, reduced hemolysis, improved red cell half-life and thus corrected anemia and mitigated disease complications of β-thalassemia syndrome2. In the present study, we evaluated RAP-536 as a monotherapy and combination therapy with HU in the murine model of sickle cell disease (βS/βS)3. SCD mice were dosed with RAP-536 (1 mg/kg, twice weekly, s.c.) or TBS vehicle (VEH) control (N=5/group) for 3 months. A combination treatment with HU (100mg/kg, i.p.) and RAP-536 (10mg/kg, s.c) twice weekly for 2 months was performed and compared with vehicle or HU monotherapy treated SCD mice. Non-symptomatic compound heterozygote (β/βS) littermates were treated similarly (N=5/group) and used as controls to confirm disease in SCD (βS/βS) mice. At study baseline, SCD mice had reduced RBC number (-28%, P<0.01) and hemoglobin (-14.5%, P<0.05) and increased reticulocytes (+50%, P<0.001) compared to compound heterozygote mice. Following one month of treatment, RAP-536 (1mg/kg) significantly reduced spleen weight (-20.5%, P<0.05), decreased serum bilirubin content (-17%, P<0.01) and cell free hemoglobin (-30.7%, P=0.06) compared to vehicle treated mice indicating decreased hemolysis. Most remarkably, blood smears from RAP-536 treated SCD mice displayed a decrease in number of irreversibly sickled erythrocytes (-66.5%, P<0.001) as well as reduced annexin V/PS exposure (-18.75%, N.S), suggesting improved membrane phospholipid asymmetry. RAP-536 treatment showed increased RBC number (+15.2%, P<0.01) and hemoglobin (+9.28%, P<0.05) compared to VEH treatment with concomitant decrease in reticulocytes (-13.5%, P< 0.05), suggestive of an increase in red cell half-life. Furthermore, histopathological analysis of spleen, kidneys and heart revealed a trend toward reduced intravascular congestion in RAP-536 treated SCD mice. Preliminary data from the combination treatment of HU and RAP-536 in SCD mice displayed additive beneficial effects as compared to HU alone. The combination of RAP-536 and HU produced a greater reduction in annexin V/PS exposure on peripheral blood cells than did HU alone compared to vehicle treatment (-35.6%, P<0.001 vs. -22.2%, N.S, respectively). Similarly, HU+RAP-536 showed a greater reduction in spleen size than HU alone (-50.7%, P<0.05 vs. -20.2%, N.S) respectively, compared to vehicle treated SCD mice. Additional analyses are in progress. Taken together, these data demonstrates that RAP-536 reduces the RBC sickling and red blood cell pathology in SCD and also shows its utility as monotherapy and in combination with HU to further mitigate the disease severity. ACE-536 is currently being tested in Phase 2 clinical trials in MDS and β-thalassemia patients, and merits evaluation as a therapy for SCD patients. References: Suragani RN et.al; Nature Medicine 2014; 20: 408-14Suragani RN et.al; Blood 2014; 123: 3864-72Wu LC etal; Blood. 2006; 108:1183-8. Disclosures Suragani: Acceleron Pharma Inc: Employment, Equity Ownership. Li:Acceleron Pharma Inc: Employment, Equity Ownership. Cawley:Acceleron Pharma Inc: Employment. Pearsall:Acceleron Pharma Inc: Employment, Equity Ownership. Kumar:Acceleron Pharma Inc: Employment, Equity Ownership.

EFFECT OF BW12C ON OXYGEN AFFINITY OF HAEMOGLOBIN IN SICKLE-CELL DISEASE

The Lancet ◽  
1986 ◽  
Vol 327 (8485) ◽  
pp. 831-834 ◽  
Author(s):  
A.J. Keidan ◽  
R.D. White ◽  
E.R. Huehns ◽  
I.M. Franklin ◽  
M. Joy ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Oxygen Affinity ◽  
Cell Disease

scholarly journals Impact of voxelotor (GBT440) on unconjugated bilirubin and jaundice in sickle cell disease

2018 ◽  
Vol 10 (2) ◽  
Author(s):  
Paul Telfer ◽  
Irene Agodoa ◽  
Kathleen M. Fox ◽  
Laurie Burke ◽  
Timothy Mant ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Oxygen Affinity ◽  
Well Being ◽  
Unconjugated Bilirubin ◽  
Cell Disease ◽  
Case Patient ◽  
Disease Manifestation ◽  
Patient Reported ◽  
Hemoglobin Oxygen Affinity

For many patients with sickle cell disease (SCD), jaundice is a significant clinical disease manifestation that impacts on patient well-being. We report a case of a patient with SCD and chronic jaundice treated with voxelotor (GBT440), a novel small molecule hemoglobin oxygen affinity modulator and potential disease-modifying therapy for SCD. The case patient is a 27- year-old Black male with a long history of SCD with clinical jaundice and scleral icterus. After starting voxelotor, the patient reported that his jaundice cleared within one week, and that he felt much better with more energy, and was relieved after his eyes cleared. Voxelotor reduced bilirubin and unconjugated bilirubin (by up to 76%), and hemoglobin improved from 9.9 g/dL at baseline to 11.1 g/dL at 90 days. Jaundice impacts many adults with SCD, significantly impacting self-image. Voxelotor treatment reduced bilirubin levels and improved jaundice, resulting in an improved sense of well-being in our case patient.

HENNA (Lawsonia inermis) A MEDICINAL HERB EFFECTIVE IN SICKLE CELL DISEASE

2021 ◽  
pp. 01-04
Author(s):  
KRISHNA KUMAR ◽  
Nitish Kumar ◽  
Amresh gupta ◽  
Arpita singh ◽  
Pandey Swarnima ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Red Blood Cells ◽  
Sickle Cell ◽  
Blood Cells ◽  
Oxygen Affinity ◽  
Common Disease ◽  
Cell Disease ◽  
Lawsonia Inermis ◽  
Sodium Bisulphite ◽  
Sickle Cells

Sickle cell anemia is a common disease in Oman country. In this disease, sickle-shaped cells are formed. These cells interrupt blood vessels and cause a reduction in oxygen transportation. It was founded that henna (Lawsonia inermis) can prohibit the formation of sickle cells. The Lawsone (2-Hydroxy-1,4-Naphthoquinone) is the constituents of henna which is responsible for the anti-sickling activity, by increasing the oxygen affinity of red blood cells. Hena has the anti-sickling activity which is proved by incubating aqueous and methanolic henna extracts with sickle cell disease patient's whole blood. Then for reduction to oxygen tension 2%, sodium bisulphite was added. Therefore, the percentage of sickled cells to normal red blood cells was observed at 30 minutes intervals. Henna proved a delay in the sickling process in 84% of the tested samples. Both extracts(aqueous and methanolic henna) can delay sickling for about an hour.

Alterations of Hemoglobin Fractionation in a Sickle Cell Disease Patient on Voxelotor Therapy

2020 ◽  
Vol 154 (Supplement_1) ◽  
pp. S100-S101
Author(s):  
S S Karimi ◽  
H Ni ◽  
L L Hsu
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Exchange Transfusion ◽  
Recent Literature ◽  
Disease Patient ◽  
Oxygen Affinity ◽  
Treatment Modalities ◽  
Cell Disease ◽  
Low Oxygen ◽  
Hydroxyurea Treatment

Abstract Introduction/Objective Voxelotor is a molecule that allosterically binds to the alpha-chain of hemoglobin, resulting in increased oxygen affinity. This allosteric inhibition leads to prevention of hemoglobin polymerization and sickling of red blood cells in response to low oxygen tension. Voxelotor has been used to treat patients with Sickle Cell Disease (SCD) and recent literature indicates it may contribute to complex hemoglobin fractionation (HF) elution patterns. We report a novel case of a SCD patient on concurrent Hydroxyurea, Voxelotor and chronic RBC exchange transfusion treatment and discuss the implications of these three treatment modalities on HF and monitoring of SCD. Methods A 17-year-old female with SCD complicated by frequent vaso-occlusive crisis, and avascular necrosis managed with chronic RBC exchange and Hydroxyurea. Her HF prior to initiation of Voxelotor treatment showed 3.2% HbA2, 51% HbA, 6.0% HbF, and 41% HbS. Voxelotor therapy was initiated at 1500mg/day and HF was performed 10 days later. Whole blood was collected and subjected to High Performance Liquid Chromatography (HPLC) with reflex to RBC solubility and Capillary Electrophoresis. Results HF performed post-Voxelotor therapy revealed positive sickle solubility with a complex pattern of 2.7% HbA2, 49.2% HbA, 5.3% HbF, 15.7% HbS, 0% HbC, and two additional peaks of a 6.3% peak in the window-D region (retention time of 4.34) and 20.8% of an atypical Hb peak pattern (at the retentuin time of 4.18). The results reflected a complex HF of a HbSS patient on concurrent chronic RBC exchange transfusion, hydroxyurea therapy, and Voxelotor treatment. Post Voxelotor-therapy HF revealed a reduction in HbS from 41% to 15.7% with the emergence of two additional peaks. Chronic RBC exchange transfusion and Hydroxyurea treatment account for the observed fractionation of HbA and HbF, respectively. Based on recent literature, we attribute the emergence of the two additional peaks to Voxelotor therapy. All three therapies led to reduction in HbS. Conclusion Routine HF serves as an essential modality in diagnosis and monitoring of SCD. Voxelotor treatment alters the HF profile and may cause difficulty for interpretation. With the emergence of novel therapies, it is imperative for clinicians to provide medication information to clinical laboratories and pathologists to be fully aware of the effects of current treatments to correctly interpret and monitor SCD.

scholarly journals Kinetic assay shows that increasing red cell volume could be a treatment for sickle cell disease

2017 ◽  
Vol 114 (5) ◽  
pp. E689-E696 ◽  
Author(s):  
Quan Li ◽  
Eric R. Henry ◽  
James Hofrichter ◽  
Jeffrey F. Smith ◽  
Troy Cellmer ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Cell Volume ◽  
Sickle Cell ◽  
Kinetic Method ◽  
Oxygen Affinity ◽  
Hemoglobin Concentration ◽  
Fiber Formation ◽  
Automated Image Analysis ◽  
Cell Disease ◽  
Kinetic Assay

Although it has been known for more than 60 years that the cause of sickle cell disease is polymerization of a hemoglobin mutant, hydroxyurea is the only drug approved for treatment by the US Food and Drug Administration. This drug, however, is only partially successful, and the discovery of additional drugs that inhibit fiber formation has been hampered by the lack of a sensitive and quantitative cellular assay. Here, we describe such a method in a 96-well plate format that is based on laser-induced polymerization in sickle trait cells and robust, automated image analysis to detect the precise time at which fibers distort (“sickle”) the cells. With this kinetic method, we show that small increases in cell volume to reduce the hemoglobin concentration can result in therapeutic increases in the delay time prior to fiber formation. We also show that, of the two drugs (AES103 and GBT440) in clinical trials that inhibit polymerization by increasing oxygen affinity, one of them (GBT440) also inhibits sickling in the absence of oxygen by two additional mechanisms.

scholarly journals Original Research: Diametric effects of hypoxia on pathophysiology of sickle cell disease in a murine model

2016 ◽  
Vol 241 (7) ◽  
pp. 766-771 ◽  
Author(s):  
Fang Tan ◽  
Samit Ghosh ◽  
Mario Mosunjac ◽  
Elizabeth Manci ◽  
Solomon Fiifi Ofori-Acquah
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Murine Model ◽  
Original Research ◽  
Cell Disease

scholarly journals Anomalous Renal Effects of Tin Protoporphyrin in a Murine Model of Sickle Cell Disease

2006 ◽  
Vol 169 (1) ◽  
pp. 21-31 ◽  
Author(s):  
Julio P. Juncos ◽  
Joseph P. Grande ◽  
Narayana Murali ◽  
Anthony J. Croatt ◽  
Luis A. Juncos ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Murine Model ◽  
Cell Disease ◽  
Renal Effects ◽  
Tin Protoporphyrin
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