GBT021601 improves red blood cell health and the pathophysiology of sickle cell disease in a murine model
© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd..
The pathophysiologic mechanism of sickle cell disease (SCD) involves polymerization of deoxygenated haemoglobin S (HbS), leading to red blood cell (RBC) sickling, decreased RBC deformability, microvascular obstruction, haemolysis, anaemia and downstream clinical complications. Pharmacological increase in the concentration of oxygenated HbS in RBCs has been shown to be a novel approach to inhibit HbS polymerization and reduce RBC sickling and haemolysis. We report that GBT021601, a small molecule that increases HbS-oxygen affinity, inhibits HbS polymerization and prevents RBC sickling in blood from patients with SCD. Moreover, in a murine model of SCD (SS mice), GBT021601 reduces RBC sickling, improves RBC deformability, prolongs RBC half-life and restores haemoglobin levels to the normal range, while improving oxygen delivery and increasing tolerance to severe hypoxia. Notably, oral dosing of GBT021601 in animals results in higher levels of Hb occupancy than voxelotor and suggests the feasibility of once-daily dosing in humans. In summary, GBT021601 improves RBC health and normalizes haemoglobin in SS mice, suggesting that it may be useful for the treatment of SCD. These data are being used as a foundation for clinical research and development of GBT021601.
| Errataetall: |
CommentIn: Br J Haematol. 2023 Jul;202(1):13-15. - PMID 36999892 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:202 |
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| Enthalten in: |
British journal of haematology - 202(2023), 1 vom: 05. Juli, Seite 173-183 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Dufu, Kobina [VerfasserIn] |
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| Links: |
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| Themen: |
Haemolytic anaemia |
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| Anmerkungen: |
Date Completed 27.06.2023 Date Revised 27.06.2023 published: Print-Electronic CommentIn: Br J Haematol. 2023 Jul;202(1):13-15. - PMID 36999892 Citation Status MEDLINE |
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| doi: |
10.1111/bjh.18771 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM35465862X |
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| 245 | 1 | 0 | |a GBT021601 improves red blood cell health and the pathophysiology of sickle cell disease in a murine model |
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| 500 | |a Date Revised 27.06.2023 | ||
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| 500 | |a CommentIn: Br J Haematol. 2023 Jul;202(1):13-15. - PMID 36999892 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd. | ||
| 520 | |a The pathophysiologic mechanism of sickle cell disease (SCD) involves polymerization of deoxygenated haemoglobin S (HbS), leading to red blood cell (RBC) sickling, decreased RBC deformability, microvascular obstruction, haemolysis, anaemia and downstream clinical complications. Pharmacological increase in the concentration of oxygenated HbS in RBCs has been shown to be a novel approach to inhibit HbS polymerization and reduce RBC sickling and haemolysis. We report that GBT021601, a small molecule that increases HbS-oxygen affinity, inhibits HbS polymerization and prevents RBC sickling in blood from patients with SCD. Moreover, in a murine model of SCD (SS mice), GBT021601 reduces RBC sickling, improves RBC deformability, prolongs RBC half-life and restores haemoglobin levels to the normal range, while improving oxygen delivery and increasing tolerance to severe hypoxia. Notably, oral dosing of GBT021601 in animals results in higher levels of Hb occupancy than voxelotor and suggests the feasibility of once-daily dosing in humans. In summary, GBT021601 improves RBC health and normalizes haemoglobin in SS mice, suggesting that it may be useful for the treatment of SCD. These data are being used as a foundation for clinical research and development of GBT021601 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a haemolytic anaemia | |
| 650 | 4 | |a oxygen affinity | |
| 650 | 4 | |a red blood cell health | |
| 650 | 4 | |a sickle cell disease | |
| 650 | 4 | |a sickle cell murine model | |
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| 650 | 7 | |a S88TT14065 |2 NLM | |
| 650 | 7 | |a Hemoglobins |2 NLM | |
| 650 | 7 | |a Hemoglobin, Sickle |2 NLM | |
| 700 | 1 | |a Alt, Carsten |e verfasserin |4 aut | |
| 700 | 1 | |a Strutt, Steven |e verfasserin |4 aut | |
| 700 | 1 | |a Partridge, James |e verfasserin |4 aut | |
| 700 | 1 | |a Tang, Tzechiang |e verfasserin |4 aut | |
| 700 | 1 | |a Siu, Vincent |e verfasserin |4 aut | |
| 700 | 1 | |a Liao-Zou, Hilary |e verfasserin |4 aut | |
| 700 | 1 | |a Rademacher, Peter |e verfasserin |4 aut | |
| 700 | 1 | |a Williams, Alexander T |e verfasserin |4 aut | |
| 700 | 1 | |a Muller, Cynthia R |e verfasserin |4 aut | |
| 700 | 1 | |a Geng, Xin |e verfasserin |4 aut | |
| 700 | 1 | |a Pochron, Mira Patel |e verfasserin |4 aut | |
| 700 | 1 | |a Dang, Annie Nguyen |e verfasserin |4 aut | |
| 700 | 1 | |a Cabrales, Pedro |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Zhe |e verfasserin |4 aut | |
| 700 | 1 | |a Oksenberg, Donna |e verfasserin |4 aut | |
| 700 | 1 | |a Cathers, Brian E |e verfasserin |4 aut | |
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