β-haemoglobinopathies such as sickle cell disease and β-thalassemia are among the most common genetic disorders in the world and are caused by mutations in the β-globin locus.
It was identified that increased levels of foetal haemoglobin are beneficial for patients with these disorders, reducing the severity of their symptoms. In most individuals, foetal haemoglobin is expressed from about 12 weeks gestation. It is developmentally silenced after the first year following birth and is replaced by adult haemoglobin which remains the dominant haemoglobin throughout life. This is known as globin switching. A rare, benign condition known as hereditary persistence of foetal haemoglobin (HPFH) prevents the silencing of foetal haemoglobin resulting in expression into adulthood. The increase in foetal haemoglobin in this condition results in ameliorated symptoms of β-haemoglobinopathies.
While the mechanism underlying many of the point mutations resulting in HPFH have been explored and characterised, HPFH caused by deletional mutations has yet to be well understood. We have introduced a number of naturally occurring deletional HPFH mutations into a cell model via a CRISPR-Cas9 mediated genome editing approach. Through these cell models we aim to investigate whether the deletions substantially increase HbF levels as well as explore the mechanisms involved in reversing globin switching. By developing a better mechanistic understanding of globin switching using HPFH deletional mutation cell models we aim to explore reactivation of foetal haemoglobin as a potential therapeutic strategy for patients with β-haemoglobinopathies.