Medicine

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Efficacy and safety of oral hydroxyurea in transfusion-dependent β-thalassaemia: a protocol for randomised double-blind controlled clinical trial
(BMJ Publishing Group Ltd., 2020) Yasara, N.; Wickramarathne, N.; Mettananda, C.; Manamperi, A.; Premawardhena, A.; Mettananda, S.
INTRODUCTION: Despite being one of the first diseases to be genetically characterised, β-thalassaemia remains a disorder without a cure in a majority of patients. Most patients with β-thalassaemia receive only supportive treatment and therefore have a poor quality of life and shorter life spans. Hydroxyurea, which has shown to induce fetal haemoglobin synthesis in human erythroid cells, is currently recommended for the treatment of sickle cell disease. However, its clinical usefulness in transfusion-dependent β-thalassaemia is unclear. Here, we present a protocol for a randomised double-blind controlled clinical trial to evaluate the efficacy and safety of oral hydroxyurea in transfusion-dependent β-thalassaemia. METHODS AND ANALYSIS: This single-centre randomised double-blind placebo-controlled clinical trial is conducted at the Thalassaemia Centre of Colombo North Teaching Hospital, Ragama, Sri Lanka. Adult and adolescent patients with haematologically and genetically confirmed transfusion-dependent β-thalassaemia are enrolled and randomised into the intervention or control group. The intervention group receives oral hydroxyurea 10-20 mg/kg daily for 6 months, while the control group receives a placebo which is identical in size, shape and colour to hydroxyurea without its active ingredient. Transfused blood volume, pretransfusion haemoglobin level, fetal haemoglobin percentage and adverse effects of treatment are monitored during treatment and 6 months post-treatment. Cessation or reduction of blood transfusions during the treatment period will be the primary outcome measure. The statistical analysis will be based on intention to treat. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Ethics Committee of Faculty of Medicine, University of Kelaniya (P/116/05/2018) and the trial is approved by the National Medicinal Regulatory Authority of Sri Lanka. Results of the trial will be disseminated in scientific publications in reputed journals.
Genome editing of haemopoietic stem cells for treatment of thalassaemia
(Oxford University Press, 2019) Badat, M.; Mettananda, S.; Hua, P.; Schwessinger, R.; Hughes, J.; Higgs, D.; Davies, J.
AIM: Thalassaemia is commonly due to mutations at the beta globin (HBB) locus, and this causes transfusion dependent anaemia in severe cases. A key pathophysiological factor is the imbalance of alpha and beta globin production. This results in accumulation of excess alpha globin chains, which are toxic and cause cell death. Patients who co-inherit partial deletions of the alpha globin genes with beta thalassaemia usually have a mild phenotype and are transfusion independent. We aim to develop genome editing strategies of haemopoietic stem cells to exploit this for use as part of an autologous transplant to treat thalassaemia. METHODS: CRISPR-Cas9 was used to edit the most important enhancer of the alpha globin gene to elicit a controlled reduction in alpha globin expression. In silico methods were used to define the key sequences to delete to abrogate transcription factor binding. This allowed us to develop a strategy to disrupt single transcription factor binding sites using Cas9 ribonucleoprotein. RESULTS: Our in silico approaches allowed us to define three key transcription factor binding sites within the enhancer. We were able to achieve indel efficiencies in excess of 75% as measured by next generation sequencing. This resulted in a much more controlled reduction in alpha globin expression than was achieved by deletion of the whole enhancer. DISCUSSION: In silico prediction allows the identification of the sites within enhancers that allow genome editing to be used to reduce gene expression in a highly controlled manner.
Thalassaemia: In a quest towards an ultimate cure
(Sri Lanka College of Paediatricians, 2017) Mettananda, S.
Alpha-globin as a molecular target in treatment of beta-thalassemia
(American Society of Hematology, 2015) Mettananda, S.; Gibbons, R. J.; Higgs, D. R.
The thalassemias together with sickle cell anemia and its variants are the world's most common form of inherited anemia and in economically undeveloped countries still account for tens of thousands of premature deaths every year. In developed countries, treatment of thalassemia is still far from ideal, requiring lifelong transfusion or allogeneic bone marrow transplantation. Clinical and molecular genetic studies over the past 50 years have demonstrated how co-inheritance of modifier genes, which alter the balance of α-like and β-like globin gene expression, may transform severe, transfusion dependent thalassemia into mild forms of anemia. Most attention has been paid to pathways that increase γ-globin expression and hence the production of fetal hemoglobin. Here we review the evidence that reduction of α-globin expression may provide an equally plausible approach to ameliorate clinically severe forms of β-thalassemia, in particular, the very common subgroup of patients with HbE β-thalassemia which make up approximately half of all patients born each year with severe β-thalassemia.

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