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

Donna Oksenberg, Kobina Dufu, Mira P. Patel, Chihyuan Chuang, Zhe Li, Qing Xu, Abel Silva-Garcia, Chengjing Zhou, Athiwat Hutchaleelaha, Larysa Patskovska, Yury Patskovsky, Steven C. Almo, Uma Sinha, Brian W. Metcalf, David R. Archer

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58 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)141-153
Number of pages13
JournalBritish Journal of Haematology
Volume175
Issue number1
DOIs
StatePublished - Oct 1 2016

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Keywords

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

ASJC Scopus subject areas

  • Hematology

Cite this

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), 141-153. https://doi.org/10.1111/bjh.14214