Successful gene therapy for beta-thalassaemia

22 September 2010

Beta-thalassaemia is a serious genetic disease and particularly common among populations of Mediterranean, Middle Eastern and Asian descent. There is therefore a considerable driving force behind efforts to develop effective gene therapy, and various approaches have been taken (see previous news).

Now, a new paper in Nature reports on a patient with severe beta-thalassaemia in whom a gene therapy procedure has removed the need for monthly blood transfusions, the only available treatment other than tissue-matched bone marrow transplantation, if a suitable donor can be found.
The gene therapy took place almost three years earlier, and involved removal and treatment of blood precursor cells (haematopoietic stem cells or HSCs) from two adult subjects [Cavazzana-Calvo M et al. (2010) Nature 467(7313):318-22]. The treatment delivered a virus-like gene therapy vector containing a modified form of the human beta-globin gene encoding a protein designed to restore normal function, whilst still being distinguishable from normal adult beta-globin proteins by specialised analysis.
The beta-thalassaemia patients each had chemotherapy to suppress the remaining, diseased HSCs left in their body, followed by transfusion of their treated HSCs. The transfused cells did not engraft and grow properly in the first patient, reportedly because they ‘had been compromised by the technical handling of the cells’, so that transfusion of other cells was necessary.
However, the second patient showed a good response to the therapy. The genetically modified HSCs grew and gave rise to increasing levels of new HSCs producing functional beta-globin protein. The patient was later able to cease receiving standard blood transfusions, and has been without a transfusion for almost two years.
The authors note that one genetically modified HSC line (comprising about half of all the cells) in which the gene therapy vector inserted into the HMGA2 gene showed increased production of the corresponding HMGA2 protein in some cells. This is normally involved in the control of gene expression, and the concern would be that it could lead to abnormal gene expression and potentially drive transformation to a cancer cell. Cancer caused by inappropriate insertion of gene therapy vectors into target cells is a significant risk for gene therapy to date (see previous news), and the patient will require life-long monitoring for this, as well as to ensure that his beta-globin levels remain high.
Comment: This is a cheering proof-of-principle showing that gene therapy can be effective as a treatment for beta-thalassaemia in humans. Obviously, the long-term outcome for the patient in question is not yet known, and the general efficacy and safety will need to be assessed for larger numbers of patients in further carefully controlled clinical trials. Gene therapy is, however, moving forward.

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