We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease.
- Authors
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.
- 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.
- Subjects
SICKLE cell anemia; DEOXYHEMOGLOBIN; PATHOLOGICAL physiology; ERYTHROCYTES; RETICULOCYTES
- Publication
British Journal of Haematology, 2016, Vol 175, Issue 1, p141
- ISSN
0007-1048
- Publication type
Article
- DOI
10.1111/bjh.14214