Harnessing RNA interference in gene therapy vectors for β-thalassaemia

The β-haemoglobin disorders such as β thalassaemia, haemoglobin E (HbE), and sickle cell disease (SCD) are among the most prevalent inherited disorders worldwide. The conditions are the result of mutations in the adult β-globin gene, leading to production of either aberrant or insufficient β-globin protein. Symptoms appear in the first year of life, the period when fetal haemoglobin (HbF) is replaced by the adult form (HbA), leaving the patient dependent upon the mutated adult β-globin gene. Much of the pathology of this disease is due to excess α-globin chains forming toxic insoluble precipitates in erythroid cells resulting in cell death, ineffective erythropoiesis and severe anaemia. Interestingly, restoration of balanced globin protein synthesis through the reduction of α-globin expression can ameliorate the disease phenotype, exemplified by individuals who co-inherit α- and β-thalassaemia. This definitive observation forms the basis of a novel therapeutic strategy for β-thalassaemia, involving not an elimination but a targeted reduction of complementary α-globin chains, to mimic co-inheritance of α- and β thalassaemia. While the benefits of increased β-globin expression in the context of β-thalassaemia are very clear, decreasing α-globin expression has not yet been extensively investigated. This project aims to develop novel gene therapy strategies harnessing RNAi in gene therapy vectors for β-thalassaemia. Initial studies will be conducted in vitro using both cell lines and primary haematopoietic stem cells. Further studies will also be conducted in vivo using our unique humanised β-thalassaemia mouse models and patient-derived cells.