Synergistic Silencing Of Alpha-Globin And Induction Of Gamma-Globin By Histone Deacetylase Inhibitor, Vorinostat As A Potential Therapy For Beta-Thalassaemia

beta-Thalassaemia is one of the most common monogenic diseases with no effective cure in the majority of patients. Unbalanced production of alpha-globin in the presence of defective synthesis of beta-globin is the primary mechanism for anaemia in beta-thalassaemia. Clinical genetic data accumulated over three decades have clearly demonstrated that direct suppression of alpha-globin and induction of gamma-globin are effective in reducing the globin chain imbalance in erythroid cells hence improving the clinical outcome of patients with beta-thalassaemia. Here, we show that the histone deacetylase inhibitor drug, vorinostat, in addition to its beneficial effects for patients with beta-thalassaemia through induction of gamma-globin, has the potential to simultaneously suppress alpha-globin. We further show that vorinostat exhibits these synergistic beneficial effects in globin gene expression at nanomolar concentrations without perturbing erythroid expansion, viability, differentiation or the transcriptome. This new evidence will be helpful for the interpretation of existing clinical trials and future clinical studies that are directed towards finding a cure for beta-thalassaemia using vorinostat.