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UCL Great Ormond Street Institute of Child Health

Great Ormond Street Institute of Child Health

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Treating congenital diseases before birth

Supervisors names
Stavros Loukogeorgakis
Joe Davidson

Background: Inherited metabolic disorders and congenital haemoglobinopathies represent a significant cause of morbidity and mortality in children. While therapy for many conditions is possible with Bone Marrow Transplant (BMT); this has a treatment burden of Graft vs Host Disease as well as needing a matched donor. In Utero Transplantation (IUT) is able to navigated these issues in that treatment can be delivered without immune suppression or the need for donor-matching.

Aims and Objectives: Working in a variety of mouse models of IUT, the project aims to explore the way that donor HSC behave within the fetal recipient in order to produce functional haematopoietic chimerism. The student will explore how HSC behave using traditional flow cytometry methods as well as next generation sequencing across timepoints after IUT in both healthy and disease models (alpha-Thalassaemia and Krabbe Disease).
Methods: Technical aspects of IUT experiments will be performed initially by one of the supervisory individuals (SL or JD) with a possibility of learning the technique. Students will be expected to learn animal handling and husbandry including colony genotyping. Students will learn how to perform complex flow cytometry analysis and develop new methods for histopathological analysis. Finally, an opportunity to learn pipeline and analytical steps for single-cell analysis will be possible although not essential.

Timeline: Prior to commencing, the student should make initial steps to undertake the relevant animal handling and experimentation course (paid for by the team). As many of the experimental platforms are already up and running, there will be an opportunity to be immediately involved in relevant experiments to generate data, with "on the job" learning of techniques to gain full independence for many of the aspects of the work.

References: 

  • Merianos DJ et al. Maternal alloantibodies induce a postnatal immune response that limits engraftment following in utero hematopoietic cell transplantation in mice. Journal of Clinical Investigation. 2009;119(9):2590–600. 
  • Shangaris P et al. Long-Term Hematopoietic Engraftment of Congenic Amniotic Fluid Stem Cells after in Utero Intraperitoneal Transplantation to Immune Competent Mice. Stem Cells Dev. 2018;27(8):515–23. 
  • Loukogeorgakis SP et al. In Utero Transplantation of Expanded Autologous Amniotic Fluid Stem Cells Results in Long-Term Hematopoietic Engraftment. Stem Cells. 2019 Sep 22;37(9):1176–88.
  • Loukogeorgakis SP et al. Donor cell engineering with GSK3 inhibitor-loaded nanoparticles enhances engraftment after in utero transplantation. Blood. 2019 Nov 28;134(22):1983–95.

Contact
Stavros Loukogeorgakis (stavros.loukogeorgakis@gosh.nhs.uk; s.loukogeorgakis@ucl.ac.uk)