Haemoglobinopathies as a target for Fetal Transplantation

Background
Over 200 babies are born each year in the UK with inherited blood disorders such as haemoglobinopathies. These disorders affect the oxygen carrying part of the red blood cell. Thalassaemia is one of the most common. Treatment involves regular blood transfusions throughout the life of the patient. This can lead to multiple issues in later life including diabetes, heart conditions and thinning of the bone due to excess accumulation of iron in the tissues. Furthermore, many individuals require complex multi-disciplinary care and have considerable disruption to school and work due to hospital admissions and problems with symptoms. At present, Thalassaemia can be cured with a Bone Marrow Transplant. This involves giving donor stem cells, however this is not offered very often because there are significant risks involved. The immune system of the patient and the immune cells in the transplant can both cause significant problems, including death. There is also a considerable risk of Graft vs Host Disease, wherein the transplanted cells begin to attack the recipient. For that reason, there is a lot of research into the way that the immune systems function in this setting.
Fetal Stem Cell Transplant
The immune system of the fetus is unique, because it is still learning what it needs to call a friend ("self-recognition" of "tolerance") or an enemy. Research has already shown that giving a transplant at this time can give tolerance to the transplant without needing to give any medication to suppress the immune system, avoiding many of the risks of post-natal bone marrow transplant. However we have not been able to use this to treat a model for haemaglobinopathies like thalassaemia.
Our Research
We know that stem cells cannot engraft or induce tolerance alone, so my research aims to look at other cells within the bone marrow that allow the stem cells to stick or "engraft" within the fetus. We will do this by performing bone marrow transplants into fetal mice and studying how the transplanted cells behave in the recipient. After identifying the important cells in this process we will then attempt to treat a mouse model of thalassaemia with a fetal transplant. If successful, the mice will express two different types of red blood cell (Thalassaemia cells and cells from the transplant). We will be able to study these by examining both mice blood and bone marrow. Importantly, having healthy blood cells present from the donor will means these mice do not get symptoms of thalassaemia - including anaemia and heart muscle damage.
Implications of this work
If we are able to identify a specific cell that induces tolerance for fetal transplantation, we will be much closer to delivering a treatment into humans for thalassemia and other devastating diseases which can be diagnosed prenatally. Indeed, while patients with the former will survive to adulthood, there are many other conditions (such as rare metabolic conditions) where the disease may be progressing during development. Fetal stem cell transplant would offer a cure for these conditions and therefore also a better outcome by the time the baby is born.

Background: Models for fetal transplantation are well established, however long-term engraftment of a haematopoeitic stem cell (HSC) allograft has yet to be demonstrated. The mouse model for fetal transplant has closer similarity to human immune development than many published larger animal models (e.g. sheep.) We aim to study allogeneic HSC engraftment in wild type mice and a mouse model of thalassaemia. While whole bone marrow transplantation is able to deliver both engraftment and tolerance, our preliminary data demonstrates that pure HSC are not - suggesting a further cell type is critical in establishing therapeutic effect.
Objectives: We plan to identify the tolerogenic cell type within the lineage depleted portion of the bone marrow and deliver this with HSC to fetal mice, demonstrating engraftment levels similar to whole bone marrow. We will then deliver this regimen to a mouse model of thalassaemia.
Methods: I will employ a well-studied method of intravascular injection of cells and, using fetal and postnatal endpoints, examine the passage of transplanted cells within the host, as well as study donor-specific tolerance and long-term engraftment of the transplant. Having identified a tolerogenic cell population, I will then deliver a co-transplant of HSC and tolerogenic cells to treat a humanised mouse model of thalassaemia. We will assess the efficacy of this treatment by studying chimerism of haemoglobin in the recipient mice and examining effects on composition of organs such as the heart, liver and spleen.
Opportunities of this study: This model for phenotypic correction would be applicable to other haemoglobinopathies (e.g. Sickle Cell Disease) and enzyme storage disease (e.g. Mucopolysaccharidosis); some of these conditions, although rare, pose a significant challenge to the clinician as often a degree of antenatal injury will occur as a result of the defect - as such, the benefits of a successful fetal transplant may be even more measurable.