AbstractBackground: The most common forms of hereditary haemoglobinopathies are (i) sickle cell disease (SCD) corresponding to structural aberrations of the β-globin gene (HBB) and (ii) β-thalassaemia caused by globin chain imbalance due to HBB absence or underproduction. Recent advances in haematopoietic stem cell (HSC)-based gene therapy (GT) have been promising, thus, correction by lentiviral vector (LV)-mediated GT is being developed for these β-globinopathies.
Primary objective: Functional analysis of LVs based on the prototypical GLOBE construct containing novel β-globin gene designs to increase HBB expression for increased efficacy of gene therapy.
Secondary objective: Generation of a conditionally immortalised erythroid progenitor cell line from β-thalassaemia patients.
Results: A higher HBB transgene expression per vector copy with the enhanced GLOBE LV designs in erythroid cell culture assays was obtained.
A conditionally immortalised erythroid cell clone from a β-thalassaemia HBB IVS-I-110 G>A homozygote patient-derived hCD34+ cells was successfully generated.
Conclusions: Elements that can provide higher functional efficiency of the GLOBE LV design could be introduced in LV designs for increased transgene expression following thorough evaluation aimed towards a more efficacious correction of β-globinopathies by gene therapy. A novel β-thalassaemia HBB- IVS-I-110 immortalised adult human erythroid progenitor cell line was generated which can be used as an in vitro analysis system.
|Date of Award||1 Jul 2019|
|Supervisor||Michael Antoniou (Supervisor)|