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expert reaction to study on gene therapy for beta-thalassaemia

Researchers use gene therapy – via a lentiviral vector – for patients with beta-thalassaemia, in a new study, published in the NEJM.


Prof Darren Griffin, Professor of Genetics, University of Kent, said:

“The results here are from phase 1-2 clinical trials and are incredibly promising.  The numbers are small (only 22 patients in a total of 2 studies reported here) but the fact that previously only a single patient had been treated in this way means that this report is a significant advance.  In terms of safety, the results seem very promising and in terms of efficacy, equally so. The fact that the majority of patients could discontinue blood transfusions is a significant boon to their quality of life as a result of this treatment. Moreover it paves the way for much larger studies and hence a greater number of patients benefitting.”


Prof Douglas Higgs, Professor of Haematology and Director of the MRC Haematology Unit, University of Oxford, said:

“This important study from Thompson et al. describes the state-of-the-art for gene therapy to cure common, severe forms of inherited anaemia resulting from disorders affecting the genes which encode the red cell pigment haemoglobin. The work is based on over 40 years of research from this field discovering how the haemoglobin genes are normally switched on in red cells, and how to harness viruses as vectors to insert new copies of these genes into blood stem cells from which the red cells are produced.

“One issue not discussed in the paper is the extent to which the increased level of haemoglobin comes from the newly inserted genes and to what extent other globin genes, normally expressed in fetal life but silenced in adult life, are reactivated by the process of stem cell transplantation itself. Even though this is the best we can achieve at the moment, not all patients become free of transfusions and we still do not know the long-term effects of manipulating the genome of stem cells in this way. A major question hanging over this approach, which is hugely expensive,  is whether this procedure, which involves killing off abnormal stem cells to replace them with modified stem cells, will ever become clinically possible in developing countries where the majority of these disorders of haemoglobin occur.”


Prof Irene Roberts, Professor of Paediatric Haematology, University of Oxford, said:

“This study published in the New England Journal of Medicine is important because it provides the first convincing evidence that gene therapy using a lentiviral vector can be used to effectively treat, and potentially cure, patients with the blood disorder b-thalassaemia. This disease is caused by inherited defects in the beta-globin gene, an essential component of red blood cells, and it is one of the most common genetic blood disorders in the world.

“Most patients with beta-thalassaemia rely for their survival on monthly red blood transfusions; a small number can be cured by stem cell transplantation if a suitable stem cell donor can be found. This study shows that, in principle, all patients with b-thalassaemia could be cured, or at least substantially improved, by ‘engineering’ their own stem cells. Although, it is 8 years since publication of the first evidence that b-thalassaemia stem cells could be modified using a beta-globin lentivirus, only a single patient was successfully treated at that time and there were doubts about the safety of this approach.

“In this new study, two teams led by investigators in France and the United States pooled their expertise and results to test the efficacy and safety of a modified lentivirus to deliver a normal beta-globin gene into thalassaemia patients’ stem cells in 22 patients. As the b-globin was ‘tagged’ by a unique marker, the investigators could prove that at least some stem cells had been successfully ‘engineered’ in all 22 patients, although the amount of beta-globin they were able to produce was very variable. Nevertheless, red blood cell production in 15 patients improved to such an extent that transfusions could be stopped altogether. Several of the other patients needed fewer transfusions after gene therapy than before.

“Reducing, or stopping transfusions is important for patients with beta-thalassaemia because they are a ‘double-edged sword- essential for survival but also responsible for life-changing, life shortening side effects. This means that the results are very encouraging. Whether, as the accompanying editorial suggests, this means that the results can be applied more generally to the estimated 288,000 beta-thalassaemic patients worldwide, mostly living in under-resourced countries, is debatable. The success of the study relied on obtaining large numbers of stem cells from patients, manipulating these cells under strictly controlled laboratory conditions, administering high doses of chemotherapy and monitoring these patients very closely in highly specialised hospitals. The costs of this trial, and of delivering such therapy outside of the clinical trial setting, are not clear and difficult to predict if commercial companies provide the engineered stem cells. Finally, although there was good evidence of short-term safety at a clinical level and the laboratory investigations were reassuring in that no clonal dominance related to vector integration was observed, the authors of the study rightly emphasise the importance of collecting detailed long-term efficacy and safety data before the true place of this approach in the management of patients with beta-thalassaemia can be confirmed.”


* ‘Gene Therapy in Patients with Transfusion-Dependent β-Thalassemia’ by A. A. Thompson et al. published in The New England Journal of Medicine on Wednesday 18th April. 


All our previous output on this subject can be seen at this weblink:


Declared interests

Prof Darren Griffin: No COI

Prof Irene Roberts: No declarations

Prof Douglas Higgs: No declarations of interest

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