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Dissecting the mechanism of action of thalidomide analogs in patients with the beta-haemoglobinopathies

Code: BC-DTP_2026_39

Title: Dissecting the mechanism of action of thalidomide analogs in patients with Sickle cell disease and beta-thalassaemia

Primary Supervisor: Mohsin Badat

Email: m.badat@qmul.ac.uk

Institute: Blizard Institute

Secondary Supervisor: Kevin Roualt-Pierre

Email: k.rouault-pierre@qmul.ac.uk

Institute: Barts Cancer Institute

Lay Summary:

The beta-haemoglobinopathies – Sickle Cell Disease and Thalassaemia - are the most common genetic disorders in the world, and thousands of patients with these diseases live in East London and are treated at Bartshealth Hospitals. Treatments for these conditions remain extremely limited. They are caused by an abnormality in either the structure or amount of normal haemoglobin produced by the body. Careful research has proved that fetal haemoglobin - a form of haemoglobin that is normally switched off at birth - is highly beneficial for patients who can still produce it as adults, usually due to rare mutations or certain medications.  One such medication, thalidomide and its related compound pomalidomide have been shown to be highly effective in small studies in other parts of the world. Despite this we do not have a full understanding of why it works, as it is known as a drug that is most commonly used as an anti-cancer drug in myeloma. In this project we aim to use cells from patients in our clinic to look at the mechanisms causing fetal haemoglobin to rise with thalidomide use. We will use state-of-the-art so-called ‘epigenetic’ techniques to look at the genetic landscape around the key genes involved, as well as looking at the quality-control pathways involving proteins in the cell that are changed when thalidomide is used. Through this approach we hope to identify new targeted treatments for the haemoglobinopathies that are more efficient and have fewer side effects.

Aims and Objectives:
 
1- Assessment of epigenetic and transcriptomic changes at the beta-globin/erythroid gene loci in IMiD-treated erythroid cells. 
2 – Identification of erythroid-specific proteins associated with or ubiquitinated by IMiD-CRL4CRBN, which control gamma-globin and erythropoiesis.  
3 - Manipulation of target proteins through gene editing/pharmacological interference in a bone marrow organoid system 

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