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GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease.
Br J Haematol. 2016 10; 175(1):141-53.BJ

Abstract

A major driver of the pathophysiology of sickle cell disease (SCD) is polymerization of deoxygenated haemoglobin S (HbS), which leads to sickling and destruction of red blood cells (RBCs) and end-organ damage. Pharmacologically increasing the proportion of oxygenated HbS in RBCs may inhibit polymerization, prevent sickling and provide long term disease modification. We report that GBT440, a small molecule which binds to the N-terminal α chain of Hb, increases HbS affinity for oxygen, delays in vitro HbS polymerization and prevents sickling of RBCs. Moreover, in a murine model of SCD, GBT440 extends the half-life of RBCs, reduces reticulocyte counts and prevents ex vivo RBC sickling. Importantly, oral dosing of GBT440 in animals demonstrates suitability for once daily dosing in humans and a highly selective partitioning into RBCs, which is a key therapeutic safety attribute. Thus, GBT440 has the potential for clinical use as a disease-modifying agent in sickle cell patients.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Oksenberg D
Global Blood Therapeutics Inc., South San Francisco, CA, USA. doksenberg@globalbloodtx.com.
Dufu K
Global Blood Therapeutics Inc., South San Francisco, CA, USA.
Patel MP
Global Blood Therapeutics Inc., South San Francisco, CA, USA.
Chuang C
Cytokinetics, South San Francisco, CA, USA.
Li Z
Global Blood Therapeutics Inc., South San Francisco, CA, USA.
Xu Q
Global Blood Therapeutics Inc., South San Francisco, CA, USA.
Silva-Garcia A
Global Blood Therapeutics Inc., South San Francisco, CA, USA.
Zhou C
Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, GA, USA.
Hutchaleelaha A
Global Blood Therapeutics Inc., South San Francisco, CA, USA.
Patskovska L
Albert Einstein College of Medicine, Bronx, NY, USA.
Patskovsky Y
Albert Einstein College of Medicine, Bronx, NY, USA.
Almo SC
Albert Einstein College of Medicine, Bronx, NY, USA.
Sinha U
Global Blood Therapeutics Inc., South San Francisco, CA, USA.
Metcalf BW
Global Blood Therapeutics Inc., South San Francisco, CA, USA.
Archer DR
Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, GA, USA.

MeSH

Anemia, Sickle CellAnimalsAntisickling AgentsBlood Gas AnalysisCell SurvivalDisease Models, AnimalErythrocytes, AbnormalHemoglobin, SickleHumansMiceOxygenProtein Aggregation, PathologicalProtein Binding

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27378309

Citation

Oksenberg, Donna, et al. "GBT440 Increases Haemoglobin Oxygen Affinity, Reduces Sickling and Prolongs RBC Half-life in a Murine Model of Sickle Cell Disease." British Journal of Haematology, vol. 175, no. 1, 2016, pp. 141-53.
Oksenberg D, Dufu K, Patel MP, et al. GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease. Br J Haematol. 2016;175(1):141-53.
Oksenberg, D., Dufu, K., Patel, M. P., Chuang, C., Li, Z., Xu, Q., Silva-Garcia, A., Zhou, C., Hutchaleelaha, A., Patskovska, L., Patskovsky, Y., Almo, S. C., Sinha, U., Metcalf, B. W., & Archer, D. R. (2016). GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease. British Journal of Haematology, 175(1), 141-53. https://doi.org/10.1111/bjh.14214
Oksenberg D, et al. GBT440 Increases Haemoglobin Oxygen Affinity, Reduces Sickling and Prolongs RBC Half-life in a Murine Model of Sickle Cell Disease. Br J Haematol. 2016;175(1):141-53. PubMed PMID: 27378309.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease. AU - Oksenberg,Donna, AU - Dufu,Kobina, AU - Patel,Mira P, AU - Chuang,Chihyuan, AU - Li,Zhe, AU - Xu,Qing, AU - Silva-Garcia,Abel, AU - Zhou,Chengjing, AU - Hutchaleelaha,Athiwat, AU - Patskovska,Larysa, AU - Patskovsky,Yury, AU - Almo,Steven C, AU - Sinha,Uma, AU - Metcalf,Brian W, AU - Archer,David R, Y1 - 2016/07/05/ PY - 2016/02/25/received PY - 2016/04/25/accepted PY - 2016/7/6/entrez PY - 2016/7/6/pubmed PY - 2017/5/16/medline KW - haemoglobin KW - oxygen affinity KW - pharmacokinetics KW - sickle cell disease KW - sickle cell murine model KW - therapeutic SP - 141 EP - 53 JF - British journal of haematology JO - Br J Haematol VL - 175 IS - 1 N2 - A major driver of the pathophysiology of sickle cell disease (SCD) is polymerization of deoxygenated haemoglobin S (HbS), which leads to sickling and destruction of red blood cells (RBCs) and end-organ damage. Pharmacologically increasing the proportion of oxygenated HbS in RBCs may inhibit polymerization, prevent sickling and provide long term disease modification. We report that GBT440, a small molecule which binds to the N-terminal α chain of Hb, increases HbS affinity for oxygen, delays in vitro HbS polymerization and prevents sickling of RBCs. Moreover, in a murine model of SCD, GBT440 extends the half-life of RBCs, reduces reticulocyte counts and prevents ex vivo RBC sickling. Importantly, oral dosing of GBT440 in animals demonstrates suitability for once daily dosing in humans and a highly selective partitioning into RBCs, which is a key therapeutic safety attribute. Thus, GBT440 has the potential for clinical use as a disease-modifying agent in sickle cell patients. SN - 1365-2141 UR - https://www.unboundmedicine.com/medline/citation/27378309/GBT440_increases_haemoglobin_oxygen_affinity_reduces_sickling_and_prolongs_RBC_half_life_in_a_murine_model_of_sickle_cell_disease_ DB - PRIME DP - Unbound Medicine ER -