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.