Project ID CM-HD2024_16


Co Supervisor 1A Faculty of Life Sciences & Medicine, School of Life Course & Population Sciences, Department of Women & Children’s HealthWebsite

Co Supervisor 1B Faculty of Life Sciences & Medicine, School of Life Course & Population Sciences, Department of Women & Children’s HealthWebsite

Additional Supervisor Dr Panicos Shangaris

Hydroxyurea in pregnancies complicated by sickle cell disease.

Sickle Cell Disease (SCD) is a blood disorder with a high disease-burden, affecting individuals of Black ancestry, and is associated with adverse pregnancy outcomes including maternal mortality (6x), pre-eclampsia & preterm birth (2x), growth restriction & stillbirth (4x), and higher resource utilisation (7x). The sole recommended intervention in pregnancy, prophylactic blood transfusions, carries risks of alloimmunization (30%), hyperhaemolysis, iron overload, and cost/limited availability. Hydroxyurea (HU), commonly used in non-pregnant individuals with SCD to reduce pain crises, decrease the risk of acute chest syndrome, improve anemia, preserve long-term organ function, lower the risk of stroke, and potentially extend lifespan, has shown benefits in pregnant patients by reducing preterm birth, pre-eclampsia, and fetal demise and improving maternal hemoglobin levels, with no reported side effects in human case reports. Concerns about potential teratogenicity exist, though animal studies have utilised doses ranging from 5 to 60 gr/kg, whereas the adult dose during pregnancy is 1.5 gr/kg.
We aim to explore the effects of HU in pregnancy using a mouse model of SCD (Townes model) and assess haematological parameters and pregnancy/neonatal outcomes at relevant doses. The student will obtain a Home office Personal Licence expertise in mouse handling, drug administration, experimental planning, disease monitoring, bench laboratory techniques, histopathological analysis and data collection/analysis and presentation/manuscript preparation.

Objective for each year of the study:
Year 1: Literature and systematic review on experience with HU in pregnancies complicated by SCD. Obtain Project Licence and establish experimental design, characterise the mouse model, and perform baseline assessments.
Year 2: Administer HU to pregnant mice (SCD and control), monitor their health and collect relevant data, evaluating treatment effectiveness/complications.
Year 3: Investigate the mechanisms of hydroxyurea’s long and short effects, assess fetal/neonatal outcomes, and compare results with controls. Prepare for a Phase I clinical trial.
Year 4: Analyse and interpret data, prepare a manuscript for publication, write the doctoral thesis, and present and defend the research findings during a viva examination.

Representative Publications

1) Intravenous immunoglobulin in the management of severe early onset red blood cell alloimmunization. Vlachodimitropoulou E, Lo TK, Bambao C, Denomme G, Seaward GR, Windrim R, Tessier F, Kelly E, Van Mieghem T, Ryan G. Br J Haematol. Jan 2023. DOI: 10.1111/bjh.18449. 2) Non-invasive MRI biomarkers for the early assessment of iron overload in a humanized mouse model of β-thalassemia. Jackson LH, Vlachodimitropoulou E, Shangaris P, Roberts TA, Ryan TM, Campbell-Washburn AE, David AL, Porter JB, Lythgoe MF, Stuckey DJ. Feb 2017. Nature Sci Rep. DOI:10.1038/srep43439. 3) Synergistic intracellular iron chelation combinations: mechanisms and conditions for optimizing iron mobilization. Vlachodimitropoulou Koumoutsea E, Garbowski M, Porter JBr J Haematol. Sept 2015. DOI: 10.1111/bjh.13512.
1) Evidence-based management of pregnant women with sickle cell disease in high-income countries. Eugene Oteng-Ntim & Panicos Shangaris. Dec 2022. DOI: 10.1182/hematology.2022000378. 2) In utero Therapy for the Treatment of Sickle Cell Disease: Taking Advantage of the Fetal Immune System. Cortabarria ASV, Makhoul L, Strouboulis J, Lombardi G, Oteng-Ntim E, Shangaris P. Jan 2021. DOI: 10.3389/fcell.2020.624477. 3) Shangaris P, Loukogeorgakis SP, Subramaniam S, Flouri C, Jackson LH, Wang W, Blundell MP, Liu S, Eaton S, Bakhamis N, Ramachandra DL, Maghsoudlou P, Urbani L, Waddington SN, Eddaoudi A, Archer J, Antoniou MN, Stuckey DJ, Schmidt M, Thrasher AJ, Ryan TM, De Coppi P, David AL. In Utero Gene Therapy (IUGT) Using GLOBE Lentiviral Vector Phenotypically Corrects the Heterozygous Humanised Mouse Model and Its Progress Can Be Monitored Using MRI Techniques. Sci Rep. 2019 Aug 12;9(1):11592. doi: 10.1038/s41598-019-48078-4. Erratum in: Sci Rep. 2019 Dec 24;9(1):20214. PMID: 31406195; PMCID: PMC6690943.