Effects of hydroxyurea on microvascular flow and epigenomics in SCD
Research type
Research Study
Full title
Evaluation of effects of hydroxyurea on (1) microvascular flow using a novel microfluidic system and (2) epigenetic markers in Sickle Cell Disease.
IRAS ID
128238
Contact name
Rebecca Oakey
Contact email
Sponsor organisation
King's College London
Research summary
Sickle cell disease (SCD) is an inherited blood disorder, caused by abnormal haemoglobin referred to as HbS resulting in red blood cells (RBCs) to become rigid and sickle-shaped. The hallmark of SCD is acute painful episodes called “vaso-occlusive crises”, caused by blockage of blood vessels that supply body tissues, which can also lead to multi-organ damage.
Although vaso-occlusion is initiated by adhesion of sickled RBCs to the blood vessel wall, other cells and molecular pathways are also involved, including white blood cells (WBCs) and platelets.
Hydroxyurea (HU) is a drug therapy that is widely used in the long term treatment and prevention of many of the complications of SCD. The mechanism of action of HU in SCD is not fully understood. One mode of action is to promote an increase in foetal haemoglobin (HbF) that inhibits the sickling process, resulting in fewer sickled RBC. A second mode of action is reduction in number of WBCs and adhesion molecules produced by WBCs and blood vessel wall cells. It is not clear why only 60-80% patients have a clinical response to HU. We aim to investigate more novel effects of hydroxyurea in two different ways:
First, using a microfluidics platform that simulates the microcirculatory environment to improve our understanding of any microvascular disease. Using a novel model of the microcirculation we will compare the flow rate of blood from a patient sample taken prior to commencing hydroxyurea treatment with a sample taken after the patient is stabilised on HU, allowing an unparalleled opportunity to examine the effects of hydroxyurea on the sickle microvascular network.
Second, on an epigenetics level. HU alters blood profile values by changing expression of the genes that control these parameters i.e. HbF, WBCs. Investigation of the epigenomic profile (methylation and expression patterns) before and after HU may provide insights into its mechanism.
REC name
South Central - Oxford C Research Ethics Committee
REC reference
14/SC/1175
Date of REC Opinion
30 Jul 2014
REC opinion
Favourable Opinion