期刊
BRITISH JOURNAL OF HAEMATOLOGY
卷 175, 期 1, 页码 141-153出版社
WILEY
DOI: 10.1111/bjh.14214
关键词
sickle cell disease; haemoglobin; oxygen affinity; therapeutic; sickle cell murine model; pharmacokinetics
类别
资金
- Emory + Children's Pediatric Research Center Flow Cytometry Core
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 chain of Hb, increases HbS affinity for oxygen, delays invitro 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 exvivo 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. This article is cited in the Editorial Comment published in issue 174:4 ().
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据