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Br J Haematol. 2016 Oct;175(1):141-53. doi: 10.1111/bjh.14214. Epub 2016 Jul 5.

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

Author information

1
Global Blood Therapeutics Inc., South San Francisco, CA, USA. doksenberg@globalbloodtx.com.
2
Global Blood Therapeutics Inc., South San Francisco, CA, USA.
3
Cytokinetics, South San Francisco, CA, USA.
4
Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, GA, USA.
5
Albert Einstein College of Medicine, Bronx, NY, USA.

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.

KEYWORDS:

haemoglobin; oxygen affinity; pharmacokinetics; sickle cell disease; sickle cell murine model; therapeutic

PMID:
27378309
DOI:
10.1111/bjh.14214
[Indexed for MEDLINE]

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