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Development of a novel therapeutic for the treatment of sickle cell anaemia

RCSI StAR International PhD Programme Research Projects

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Dr M Brennan , Prof M Devocelle Applications accepted all year round Competition Funded PhD Project (Students Worldwide)

About the Project

Sickle cell anaemia is a chronic condition that is expensive to treat and requires significant clinical intervention and management. Patients in crisis need acute management that often requires hospitalization. Furthermore, damage to the vasculature leads to joint and organ damage that require frequent monitoring and treatment. Currently patients can be cured by bone marrow ablation followed by a transplant if a match can be found. Unfortunately, this process is very costly, dependent on a donor match and only has a 90% survival rate. This treatment is also only available in specialized treatment centers.

Sickle cell anaemia is a disorder resulting from a mutation in the β-chain of haemoglobin. Haemoglobin is the protein responsible for carrying oxygen from the lungs to the tissues where it releases oxygen. In patients with sickle cell disease, oxygen can be successfully carried from the lungs to the tissues, but after the oxygen is released, the haemoglobin protein interacts inappropriately with other haemoglobin proteins. This results in multimers of sickle haemoglobin (HbS) forming long rigid chains which in turn causes erythrocytes to distort into the characteristic sickle shape. The sickle shaped erythrocytes are inflexible and become trapped in the capillaries causing damage to organs. The multimers are more prone to form under certain conditions such as in low oxygen conditions and during infections. The blocking of capillaries leads to severe pain in patients known as a sickle cell crisis. The crisis can cause permanent damage to organs including the brain, liver, spleen, kidneys and lungs. In 1998 the anti-cancer treatment hydroxyurea was approved for use in sickle cell disease. Hydroxyurea increases expression of the foetal haemoglobin β-like chain. As the foetal gene is a different gene to the adult one, there is no defect in this protein subunit expressed, and therefore multimer formation is disrupted and thus the red blood cells do not distort.

Although this reduces the number of hospitalizations in patients, approximately one third of patients are refractory to this therapy for a variety of reasons (Yahouédéhou SCMA et al., 2018). Hydroxyurea is not specific and therefore can also have severe side effects including liver and kidney damage as well as increased carcinogenic risk.

Using molecular modelling, we have designed peptides to disrupt haemoglobin multimer formation that can be delivered into the erythrocytes. We plan to test peptides for binding to HbS and assess the disruption of multimer formation in a cell free assay. A range of peptides and peptidomimetics derived from the parent peptide will be assessed to identify the lead peptide. The peptides are designed with a specific peptide tag for delivery into erythrocytes, therefore, we will assess delivery into erythrocytes and perform haemolysis assays in order to determine whether the peptides damage the erythrocyte membrane. We do not expect toxicity from the peptides, however, we will also test for toxicity in endothelial cells, erythrocytes and platelets. We will further test the peptides ex vivo using red blood cells from patients with sickle cell anaemia.

Successful development of an alternative therapy for patients with sickle cell disease will provide a much needed treatment that can prevent painful crisis and damage to patient’s organs.
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