Department of Paediatrics, University of Kelaniya, Thalagolla Road, Ragama, 11010, Sri Lanka.
Medical Research Council (MRC) Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, OX3 9DS, UK.
Sci Rep. 2019 Aug 12;9(1):11649. doi: 10.1038/s41598-019-48204-2.
β-Thalassaemia is one of the most common monogenic diseases with no effective cure in the majority of patients. Unbalanced production of α-globin in the presence of defective synthesis of β-globin is the primary mechanism for anaemia in β-thalassaemia. Clinical genetic data accumulated over three decades have clearly demonstrated that direct suppression of α-globin and induction of γ-globin are effective in reducing the globin chain imbalance in erythroid cells hence improving the clinical outcome of patients with β-thalassaemia. Here, we show that the histone deacetylase inhibitor drug, vorinostat, in addition to its beneficial effects for patients with β-thalassaemia through induction of γ-globin, has the potential to simultaneously suppress α-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 β-thalassaemia using vorinostat.
β-地中海贫血是最常见的单基因疾病之一，在大多数患者中尚无有效治疗方法。在β-球蛋白合成缺陷的情况下，α-球蛋白的不平衡产生是β-地中海贫血贫血的主要机制。三十多年来积累的临床遗传数据清楚地表明，直接抑制α-球蛋白和诱导γ-球蛋白的表达可有效减轻红系细胞的珠蛋白链失衡，从而改善β-地中海贫血患者的临床预后。在这里，我们表明组蛋白去乙酰化酶抑制剂药物伏立诺他，除了通过诱导γ-球蛋白对β-地中海贫血患者有益外，还具有同时抑制α-球蛋白的潜力。我们进一步表明，伏立诺他在纳米摩尔浓度下表现出这些协同的有益的珠蛋白基因表达效应，而不会扰乱红系细胞的扩增、活力、分化或转录组。这一新的证据将有助于解释现有的临床试验和未来的临床研究，这些研究旨在使用伏立诺他寻找β-地中海贫血的治疗方法。
