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Article: GBT440 reverses sickling of sickled red blood cells under hypoxic conditions

Dufu, Kobina / Oksenberg, Donna

2018 Volume 10, Issue 2, Page(s) 7419

Abstract: Sickle cell disease is characterized by hemolytic anemia, vasoocclusion and early mortality. Polymerization of hemoglobin S followed by red blood cell sickling and subsequent vascular injury are key events in the pathogenesis of sickle cell disease. ... ...

Abstract	Sickle cell disease is characterized by hemolytic anemia, vasoocclusion and early mortality. Polymerization of hemoglobin S followed by red blood cell sickling and subsequent vascular injury are key events in the pathogenesis of sickle cell disease. Sickled red blood cells are major contributors to the abnormal blood rheology, poor microvascular blood flow and endothelial injury in sickle cell disease. Therefore, an agent that can prevent and or reverse sickling of red blood cells, may provide therapeutic benefit for the treatment of sickle cell disease. We report here that GBT440, an anti-polymerization agent being developed for the chronic treatment of sickle cell disease, increases hemoglobin oxygen affinity and reverses
Language	English
Publishing date	2018-05-14
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2586645-X
ISSN	2038-8330 ; 2038-8322
ISSN (online)	2038-8330
ISSN	2038-8322
DOI	10.4081/hr.2018.7419
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Article ; Online: GBT440 improves red blood cell deformability and reduces viscosity of sickle cell blood under deoxygenated conditions.

Dufu, Kobina / Patel, Mira / Oksenberg, Donna / Cabrales, Pedro

Clinical hemorheology and microcirculation

2018 Volume 70, Issue 1, Page(s) 95–105

Abstract: Background: In sickle cell disease (SCD), polymerization of hemoglobin S (HbS) leads to the formation of rigid, non-deformable sickled RBCs. Loss of RBC deformability, sickling and irreversible membrane damage causes abnormal blood rheology, and ... ...

Abstract	Background: In sickle cell disease (SCD), polymerization of hemoglobin S (HbS) leads to the formation of rigid, non-deformable sickled RBCs. Loss of RBC deformability, sickling and irreversible membrane damage causes abnormal blood rheology, and increases viscosity which contributes to vasoocclusion and other SCD pathophysiology. GBT440 (generic name voxelotor) is a novel anti-polymerization and anti-sickling agent currently undergoing clinical evaluation for the treatment of SCD. Objective: The purpose of this study was to determine the effects of GBT440 on deformability of sickle RBCs (SS RBCs) and the hyperviscosity of sickle cell blood (SS blood). Methods: The mechanical and rheological properties of GBT440-treated SS RBCs were measured using micropipette and filtration techniques. The viscosity of sickle blood was measured using a Wells-Brookfield cone/plate viscometer. Results: GBT440 restored movement of deoxygenated SS RBCs through a gel filtration column and reduced the pressure required to pass SS RBCs through a polycarbonate filter. Moreover, GBT440 decreased the membrane shear elastic modulus of SS RBCs assessed via micropipette aspiration and reduced the hyperviscosity of SS blood under deoxygenated conditions. Conclusions: GBT440 maintains SS RBC deformability and improves SS blood viscosity by inhibiting HbS polymerization under deoxygenated conditions. These results further support development of GBT440 as a disease-modifying agent in SCD patients.
MeSH term(s)	Anemia, Sickle Cell/blood ; Blood Viscosity/genetics ; Erythrocyte Deformability/physiology ; Erythrocytes, Abnormal/physiology ; Humans
Language	English
Publishing date	2018-04-13
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1381750-4
ISSN	1875-8622 ; 1386-0291
ISSN (online)	1875-8622
ISSN	1386-0291
DOI	10.3233/CH-170340
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Article ; Online: GBT021601 improves red blood cell health and the pathophysiology of sickle cell disease in a murine model.

Dufu, Kobina / Alt, Carsten / Strutt, Steven / Partridge, James / Tang, Tzechiang / Siu, Vincent / Liao-Zou, Hilary / Rademacher, Peter / Williams, Alexander T / Muller, Cynthia R / Geng, Xin / Pochron, Mira Patel / Dang, Annie Nguyen / Cabrales, Pedro / Li, Zhe / Oksenberg, Donna / Cathers, Brian E

British journal of haematology

2023 Volume 202, Issue 1, Page(s) 173–183

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Humans ; Animals ; Mice ; Hemolysis ; Disease Models, Animal ; Oxygen ; Anemia, Sickle Cell/drug therapy ; Erythrocytes ; Hemoglobins ; Hemoglobin, Sickle
Chemical Substances	Oxygen (S88TT14065) ; Hemoglobins ; Hemoglobin, Sickle
Language	English
Publishing date	2023-03-24
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80077-6
ISSN	1365-2141 ; 0007-1048
ISSN (online)	1365-2141
ISSN	0007-1048
DOI	10.1111/bjh.18771
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Article: GBT440 Inhibits Sickling of Sickle Cell Trait Blood Under

Dufu, Kobina / Lehrer-Graiwer, Josh / Ramos, Eleanor / Oksenberg, Donna

Hematology reports

2016 Volume 8, Issue 3, Page(s) 6637

Abstract: In sickle cell trait (SCT), hemoglobin A (HbA) and S (HbS) are co-expressed in each red blood cell (RBC). While homozygous expression of HbS (HbSS) leads to polymerization and sickling of RBCs resulting in sickle cell disease (SCD) characterized by ... ...

Abstract	In sickle cell trait (SCT), hemoglobin A (HbA) and S (HbS) are co-expressed in each red blood cell (RBC). While homozygous expression of HbS (HbSS) leads to polymerization and sickling of RBCs resulting in sickle cell disease (SCD) characterized by hemolytic anemia, painful vaso-occlusive episodes and shortened life-span, SCT is considered a benign condition usually with minor or no complications related to sickling. However, physical activities that cause increased tissue oxygen demand, dehydration and/or metabolic acidosis leads to increased HbS polymerization and life-threatening complications including death. We report that GBT440, an agent being developed for the treatment of SCD, increases the affinity of oxygen for Hb and inhibits
Language	English
Publishing date	2016-09-28
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2586645-X
ISSN	2038-8330 ; 2038-8322
ISSN (online)	2038-8330
ISSN	2038-8322
DOI	10.4081/hr.2016.6637
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Article ; Online: Increased hemoglobin affinity for oxygen with GBT1118 improves hypoxia tolerance in sickle cell mice.

Dufu, Kobina / Williams, Alexander T / Muller, Cynthia R / Walser, Cynthia M / Lucas, Alfredo / Eaker, Allyn M / Alt, Carsten / Cathers, Brian E / Oksenberg, Donna / Cabrales, Pedro

American journal of physiology. Heart and circulatory physiology

2021 Volume 321, Issue 2, Page(s) H400–H411

Abstract: Therapeutic agents that increase the Hb affinity for oxygen ( ... ...

Abstract	Therapeutic agents that increase the Hb affinity for oxygen (O
MeSH term(s)	Allosteric Regulation ; Anemia, Sickle Cell/metabolism ; Animals ; Benzaldehydes/pharmacology ; Brain/metabolism ; Cerebral Cortex/metabolism ; Disease Models, Animal ; Erythrocytes/drug effects ; Hematocrit ; Hematologic Agents/pharmacology ; Hemoglobin, Sickle/drug effects ; Hemoglobin, Sickle/metabolism ; Hypoxia/metabolism ; Mice ; Mice, Transgenic ; Niacinamide/analogs & derivatives ; Niacinamide/pharmacology ; Oxygen/metabolism ; Partial Pressure
Chemical Substances	Benzaldehydes ; GBT1118 ; Hematologic Agents ; Hemoglobin, Sickle ; Niacinamide (25X51I8RD4) ; Oxygen (S88TT14065)
Language	English
Publishing date	2021-07-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	603838-4
ISSN	1522-1539 ; 0363-6135
ISSN (online)	1522-1539
ISSN	0363-6135
DOI	10.1152/ajpheart.00048.2021
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Article ; Online: The effect of the antisickling compound GBT1118 on the permeability of red blood cells from patients with sickle cell anemia.

Al Balushi, Halima / Dufu, Kobina / Rees, David C / Brewin, John N / Hannemann, Anke / Oksenberg, Donna / Lu, David C-Y / Gibson, John S

Physiological reports

2019 Volume 7, Issue 6, Page(s) e14027

Abstract: Sickle cell anemia (SCA) is one of the commonest severe inherited disorders. Nevertheless, effective treatments remain inadequate and novel ones are avidly sought. A promising advance has been the design of novel compounds which react with hemoglobin S ( ... ...

Abstract	Sickle cell anemia (SCA) is one of the commonest severe inherited disorders. Nevertheless, effective treatments remain inadequate and novel ones are avidly sought. A promising advance has been the design of novel compounds which react with hemoglobin S (HbS) to increase oxygen (O
MeSH term(s)	Anemia, Sickle Cell/blood ; Anemia, Sickle Cell/diagnosis ; Anemia, Sickle Cell/drug therapy ; Antisickling Agents/pharmacology ; Benzaldehydes/pharmacology ; Cell Size/drug effects ; Erythrocyte Membrane/drug effects ; Erythrocyte Membrane/metabolism ; Hemoglobin, Sickle/metabolism ; Hemolysis/drug effects ; Humans ; Intermediate-Conductance Calcium-Activated Potassium Channels/antagonists & inhibitors ; Intermediate-Conductance Calcium-Activated Potassium Channels/blood ; Niacinamide/analogs & derivatives ; Niacinamide/pharmacology ; Oxygen/blood ; Permeability ; Symporters/antagonists & inhibitors ; Symporters/blood ; K Cl- Cotransporters
Chemical Substances	Antisickling Agents ; Benzaldehydes ; GBT1118 ; Hemoglobin, Sickle ; Intermediate-Conductance Calcium-Activated Potassium Channels ; KCNN4 protein, human ; Symporters ; Niacinamide (25X51I8RD4) ; Oxygen (S88TT14065)
Language	English
Publishing date	2019-03-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2724325-4
ISSN	2051-817X ; 2051-817X
ISSN (online)	2051-817X
ISSN	2051-817X
DOI	10.14814/phy2.14027
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Article ; Online: Impact of Pharmacologically Left Shifting the Oxygen-Hemoglobin Dissociation Curve on Arterial Blood Gases and Pulmonary Gas Exchange During Maximal Exercise in Hypoxia.

Stewart, Glenn M / Cross, Troy J / Joyner, Michael J / Chase, Steven C / Curry, Timothy / Lehrer-Graiwer, Josh / Dufu, Kobina / Vlahakis, Nicholas E / Johnson, Bruce D

High altitude medicine & biology

2021 Volume 22, Issue 3, Page(s) 249–262

Abstract: Stewart, Glenn M., Troy J. Cross, Michael J. Joyner, Steven C. Chase, Timothy Curry, Josh Lehrer-Graiwer, Kobina Dufu, Nicholas E. Vlahakis, and Bruce D. Johnson. Impact of pharmacologically left shifting the oxygen-hemoglobin dissociation curve on ... ...

Abstract	Stewart, Glenn M., Troy J. Cross, Michael J. Joyner, Steven C. Chase, Timothy Curry, Josh Lehrer-Graiwer, Kobina Dufu, Nicholas E. Vlahakis, and Bruce D. Johnson. Impact of pharmacologically left shifting the oxygen-hemoglobin dissociation curve on arterial blood gases and pulmonary gas exchange during maximal exercise in hypoxia.
MeSH term(s)	Exercise Test ; Hemoglobins ; Humans ; Hypoxia ; Oxygen ; Oxygen Consumption ; Pulmonary Gas Exchange
Chemical Substances	Hemoglobins ; Oxygen (S88TT14065)
Language	English
Publishing date	2021-06-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	2076262-8
ISSN	1557-8682 ; 1527-0297
ISSN (online)	1557-8682
ISSN	1527-0297
DOI	10.1089/ham.2020.0159
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Zs.A 5674: Show issues

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Article ; Online: Effects of an allosteric hemoglobin affinity modulator on arterial blood gases and cardiopulmonary responses during normoxic and hypoxic low-intensity exercise.

Stewart, Glenn M / Chase, Steven / Cross, Troy J / Wheatley-Guy, Courtney M / Joyner, Michael J / Curry, Timothy / Lehrer-Graiwer, Josh / Dufu, Kobina / Vlahakis, Nicholas E / Johnson, Bruce D

Journal of applied physiology (Bethesda, Md. : 1985)

2020 Volume 128, Issue 6, Page(s) 1467–1476

Abstract: Numerous pathophysiological conditions induce hypoxemia-related cardiopulmonary perturbations, decrements in exercise capacity, and debilitating symptoms. Accordingly, this study investigated the efficacy of an allosteric hemoglobin modulator (voxelotor) ...

Abstract	Numerous pathophysiological conditions induce hypoxemia-related cardiopulmonary perturbations, decrements in exercise capacity, and debilitating symptoms. Accordingly, this study investigated the efficacy of an allosteric hemoglobin modulator (voxelotor) to enhance arterial oxygen saturation during low-intensity exercise in hypoxia. Eight normal healthy subjects (36 ± 7 yr; 73.8 ± 9.5 kg; 3 women) completed a submaximal cycling test (60 W) under normoxic ([Formula: see text]: 0.21; O
MeSH term(s)	Adult ; Exercise ; Female ; Hemoglobins ; Humans ; Hypoxia ; Male ; Oxygen ; Oxygen Consumption ; Pulmonary Gas Exchange
Chemical Substances	Hemoglobins ; Oxygen (S88TT14065)
Language	English
Publishing date	2020-04-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	219139-8
ISSN	1522-1601 ; 0021-8987 ; 0161-7567 ; 8750-7587
ISSN (online)	1522-1601
ISSN	0021-8987 ; 0161-7567 ; 8750-7587
DOI	10.1152/japplphysiol.00185.2019
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Article ; Online: A role for TREX components in the release of spliced mRNA from nuclear speckle domains.

Dias, Anusha P / Dufu, Kobina / Lei, Haixin / Reed, Robin

Nature communications

2010 Volume 1, Page(s) 97

Abstract: The TREX complex, which functions in mRNA export, is recruited to mRNA during splicing. Both the splicing machinery and the TREX complex are concentrated in 20-50 discrete foci known as nuclear speckle domains. In this study, we use a model system where ... ...

Abstract	The TREX complex, which functions in mRNA export, is recruited to mRNA during splicing. Both the splicing machinery and the TREX complex are concentrated in 20-50 discrete foci known as nuclear speckle domains. In this study, we use a model system where DNA constructs are microinjected into HeLa cell nuclei, to follow the fates of the transcripts. We show that transcripts lacking functional splice sites, which are inefficiently exported, do not associate with nuclear speckle domains but are instead distributed throughout the nucleoplasm. In contrast, pre-mRNAs containing functional splice sites accumulate in nuclear speckles, and our data suggest that splicing occurs in these domains. When the TREX components UAP56 or Aly are knocked down, spliced mRNA, as well as total polyA+ RNA, accumulates in nuclear speckle domains. Together, our data raise the possibility that pre-mRNA undergoes splicing in nuclear speckle domains, before their release by TREX components for efficient export to the cytoplasm.
MeSH term(s)	DEAD-box RNA Helicases/genetics ; HeLa Cells ; Humans ; In Situ Hybridization, Fluorescence ; Nuclear Proteins/genetics ; RNA Interference ; RNA Precursors/genetics ; RNA Splicing/genetics ; RNA, Messenger/genetics ; RNA-Binding Proteins/genetics ; Transcription Factors/genetics
Chemical Substances	ALYREF protein, human ; Nuclear Proteins ; RNA Precursors ; RNA, Messenger ; RNA-Binding Proteins ; Transcription Factors ; DDX39B protein, human (EC 3.6.1.-) ; DEAD-box RNA Helicases (EC 3.6.4.13)
Language	English
Publishing date	2010-10-19
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/ncomms1103
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Article ; Online: The proteins PDIP3 and ZC11A associate with the human TREX complex in an ATP-dependent manner and function in mRNA export.

Folco, Eric G / Lee, Chung-Sheng / Dufu, Kobina / Yamazaki, Tomohiro / Reed, Robin

PloS one

2012 Volume 7, Issue 8, Page(s) e43804

Abstract: The conserved TREX complex, which contains UAP56, Aly, CIP29, and the multi-subunit THO complex, functions in mRNA export. Recently, several putative new components of the human TREX complex were identified by mass spectrometry. Here, we investigated the ...

Abstract	The conserved TREX complex, which contains UAP56, Aly, CIP29, and the multi-subunit THO complex, functions in mRNA export. Recently, several putative new components of the human TREX complex were identified by mass spectrometry. Here, we investigated the function of two of these, PDIP3 and ZC11A. Our data indicate that both of these proteins are components of a common TREX complex and function in mRNA export. Recently, we found that both CIP29 and Aly associate with the DEAD box helicase UAP56 and with the TREX complex in an ATP-dependent manner. We now show that this is also the case for PDIP3 and ZC11A. Thus, together with previous work, our data indicate that the TREX complex participates in multiple ATP-dependent interactions.
MeSH term(s)	Adenosine Triphosphate/metabolism ; Amino Acid Sequence ; Carrier Proteins/chemistry ; Carrier Proteins/metabolism ; HeLa Cells ; Humans ; Molecular Sequence Data ; Nuclear Proteins/chemistry ; Nuclear Proteins/metabolism ; Protein Binding ; RNA Transport ; RNA, Messenger/metabolism ; RNA-Binding Proteins/chemistry ; RNA-Binding Proteins/metabolism ; Zinc Fingers
Chemical Substances	Carrier Proteins ; Nuclear Proteins ; POLDIP3 protein, human ; RNA, Messenger ; RNA-Binding Proteins ; Adenosine Triphosphate (8L70Q75FXE)
Language	English
Publishing date	2012-08-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0043804
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