Low dose iron chelation as TReatment of Oxidative damage in Sickle cell disease

Rationale:
Sickle cell disease (SCD) is a devastating inherited hemoglobinopathy, characterized by hemolysis, vaso-occlusive crises and organ damage resulting in reduced life expectancy. Oxidative stress is a major pathophysiological factor in SCD playing a significant role in the SCD-related microvascular dysfunction, vaso-occlusion, inflammation and organ damage. Chronic life-long intravascular hemolysis with the resulting excessive levels of cell-free heme and iron is the major cause of increased production of reactive oxygen species (ROS) in SCD.
The cell-free heme rapidly releases its iron which is the main driving force of redox reactions. The hydrophobic heme also rapidly intercalates into the plasma membrane of (endothelial) cells where it releases its iron. This potentiates cell damage by catalyzing non-enzymatic generation of ROS. Endothelial cells are a major target of oxidative stress in SCD, mainly due to its proximity to cell-free heme and iron.
By inactivating NO, cell-free ferrous hemoglobin reduces nitric oxide (NO) bioavailability, limiting the important vasodilative, anti-thrombotic and anti-inflammatory properties of NO.
Since the ongoing and unremitting release of iron is the major cause of oxidative stress in SCD, it is imminent to investigate the role of iron chelators as antioxidative therapy in this disease.
Iron chelators have been shown to protect various cells, including red blood cells (RBCs) and endothelial cells, against oxidative toxicity. We recently found that sequestration of free iron by the iron-chelator deferoxamine blocked activation of neutrophils and their release of neutrophil extracellular traps (NETs) by sera of SCD patients (preliminary data). NETs have been demonstrated to be toxic, especially, to endothelial cells.
In this study we will test the hypothesis that treating sickle cell patients with low doses of readily available iron chelators might reduce oxidative stress by capturing the excessively released intravascular cell-free iron. We will determine whether treatment with iron chelators results in decreased sickling of RBCs, oxidative stress, neutrophil activation, inflammation, endothelial activation and hypercoagulability and ultimately reduced disease severity. If the hypothesis is confirmed in this pilot dose-finding study, a larger randomized controlled clinical trial will be initiated.

Objective:
To study the safety and efficacy of deferasirox as treatment of oxidative stress in adult subjects with sickle cell disease.

Sickle cell disease (SCD) is a devastating inherited hemoglobinopathy, characterized by hemolysis, vaso-occlusive crises and organ damage resulting in reduced life expectancy. Oxidative stress is a major pathophysiological factor in SCD playing a significant role in the SCD-related microvascular dysfunction, vaso-occlusion, inflammation and organ damage. Chronic life-long intravascular hemolysis with the resulting excessive levels of cell-free heme and iron is the major cause of increased production of reactive oxygen species (ROS) in SCD.
The cell-free heme rapidly releases its iron which is the main driving force of redox reactions. The hydrophobic heme also rapidly intercalates into the plasma membrane of (endothelial) cells where it releases its iron. This potentiates cell damage by catalyzing non-enzymatic generation of ROS. Endothelial cells are a major target of oxidative stress in SCD, mainly due to its proximity to cell-free heme and iron.
By inactivating NO, cell-free ferrous hemoglobin reduces nitric oxide (NO) bioavailability, limiting the important vasodilative, anti-thrombotic and anti-inflammatory properties of NO.
Since the ongoing and unremitting release of iron is the major cause of oxidative stress in SCD, it is imminent to investigate the role of iron chelators as antioxidative therapy in this disease.
Iron chelators have been shown to protect various cells, including red blood cells (RBCs) and endothelial cells, against oxidative toxicity. We recently found that sequestration of free iron by the iron-chelator deferoxamine blocked activation of neutrophils and their release of neutrophil extracellular traps (NETs) by sera of SCD patients (preliminary data). NETs have been demonstrated to be toxic, especially, to endothelial cells.
In this study we will test the hypothesis that treating sickle cell patients with low doses of readily available iron chelators might reduce oxidative stress by capturing the excessively released intravascular cell-free iron. We will determine whether treatment with iron chelators results in decreased sickling of RBCs, oxidative stress, neutrophil activation, inflammation, endothelial activation and hypercoagulability and ultimately reduced disease severity. If the hypothesis is confirmed in this pilot dose-finding study, a larger randomized controlled clinical trial will be initiated.

0, 2 weeks, 4 weeks, 6 weeks, 12 weeks

Once daily deferasirox, starting with the lowest dose of 360 mg per day during 6 weeks