Discovering the molecular switch that re-activates fetal globin to cure beta-thallassaemia

β-thalassemia is characterized by reduced or absent β-globin synthesis due to mutations in the adult β-globin gene. Homozygotes for β-thalassemia mutations suffer from severe anaemia and require lifelong blood transfusions every 3-4 weeks, leading to further complications. Due to their prevalence and severity, the treatment of haemoglobinopathies has also become a global financial burden; treatment for one patient can cost up to AU$120,000 per year, and treatment of Australia's 500 patients costs over AU$60 million per year.

Other than regular transfusions, no effective treatment for the disorder exists; however, the severity of β–thalassaemia and other β-haemoglobinopathies is ameliorated in patients that have elevated levels of fetal (γ) globin. Fetal, γ-globin can bind excess α-globin, preventing its precipitation and naturally compensating for absence of β-globin. This is evidenced in individuals who have co-inherited β-globinopathies along with the benign condition hereditary persistence of fetal haemoglobin (HPFH).

We have utilised a bacterial artificial chromosome (BAC) developed by our collaborators at the Murdoch Childrens' Research Institute to generate mouse embryonic stem cell lines, which can be used for easy readout of human globin gene expression during erythroid (blood) differentiation. We are utilising this new cell culture model of human blood development to screen chemicals and gene therapies for their ability to re-activate expression of fetal globin.