Premium
GBT 440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half‐life in a murine model of sickle cell disease
Author(s) -
Oksenberg Donna,
Dufu Kobina,
Patel Mira P.,
Chuang Chihyuan,
Li Zhe,
Xu Qing,
SilvaGarcia Abel,
Zhou Chengjing,
Hutchaleelaha Athiwat,
Patskovska Larysa,
Patskovsky Yury,
Almo Steven C.,
Sinha Uma,
Metcalf Brian W.,
Archer David R.
Publication year - 2016
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.14214
Subject(s) - ex vivo , in vivo , pharmacology , reticulocyte , chemistry , in vitro , red blood cell , cell , dosing , hemoglobin , pathophysiology , hemoglobin s , immunology , sickle cell anemia , biochemistry , biology , medicine , gene , messenger rna , microbiology and biotechnology
Summary 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 ( RBC s) and end‐organ damage. Pharmacologically increasing the proportion of oxygenated HbS in RBC s may inhibit polymerization, prevent sickling and provide long term disease modification. We report that GBT 440, 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 RBC s. Moreover, in a murine model of SCD , GBT 440 extends the half‐life of RBC s, reduces reticulocyte counts and prevents ex vivo RBC sickling. Importantly, oral dosing of GBT 440 in animals demonstrates suitability for once daily dosing in humans and a highly selective partitioning into RBC s, which is a key therapeutic safety attribute. Thus, GBT 440 has the potential for clinical use as a disease‐modifying agent in sickle cell patients.