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

Research output: Contribution to journalArticle

50 Citations (Scopus)

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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Sickle Cell Anemia
Sickle Hemoglobin
Half-Life
Hemoglobins
Erythrocytes
Oxygen
Polymerization
Reticulocyte Count
Safety

Keywords

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

ASJC Scopus subject areas

  • Hematology

Cite this

GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease. / Oksenberg, Donna; Dufu, Kobina; Patel, Mira P.; Chuang, Chihyuan; Li, Zhe; Xu, Qing; Silva-Garcia, Abel; Zhou, Chengjing; Hutchaleelaha, Athiwat; Patskovska, Larysa; Patskovsky, Yury; Almo, Steven C.; Sinha, Uma; Metcalf, Brian W.; Archer, David R.

In: British Journal of Haematology, Vol. 175, No. 1, 01.10.2016, p. 141-153.

Research output: Contribution to journalArticle

Oksenberg, D, Dufu, K, Patel, MP, Chuang, C, Li, Z, Xu, Q, Silva-Garcia, A, Zhou, C, Hutchaleelaha, A, Patskovska, L, Patskovsky, Y, Almo, SC, Sinha, U, Metcalf, BW & Archer, DR 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, vol. 175, no. 1, pp. 141-153. https://doi.org/10.1111/bjh.14214
Oksenberg, Donna ; Dufu, Kobina ; Patel, Mira P. ; Chuang, Chihyuan ; Li, Zhe ; Xu, Qing ; Silva-Garcia, Abel ; Zhou, Chengjing ; Hutchaleelaha, Athiwat ; Patskovska, Larysa ; Patskovsky, Yury ; Almo, Steven C. ; Sinha, Uma ; Metcalf, Brian W. ; Archer, David R. / GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease. In: British Journal of Haematology. 2016 ; Vol. 175, No. 1. pp. 141-153.
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