PHG Foundation | Progress in gene therapy for beta-thalassaemia

Progress in gene therapy for beta-thalassaemia
22 July 2010 | By Dr Sowmiya Moorthie | Research article

Beta thalassaemia is one of the most common autosomal recessive disorders worldwide and mainly affects individuals from Mediterranean, Middle Eastern and Asian populations. It is caused by mutations in the haemoglobin beta gene leading to either a reduction in β-globin production or the absence of β-globin synthesis, and consequently abnormal haemoglobin molecules. Individuals with a severe form of this disorder - β-thalassaemia major, suffer from life threatening anaemia and require regular blood transfusions and chelation therapy to prevent iron overload. Bone marrow transplantation is also an option for treatment, but its success is dependent on the availability of compatible donor cells and the condition of the patient.

A recent study published in EMBO Molecular Medicine describes a pre-clinical trial in which gene transfer has been used to correct for the deficiency in β-globin in cells from patients with the disease [Roselli et al. (2010) EMBO Mol. Med. doi: 10.1002/emmm.201000083]. The researchers had previously developed a viral vector called GLOBE which contained the β-globin gene and could be transferred into haematopoietic stem cells (HSC), which give rise to different types of blood cells. They also showed that this resulted in the production of β–globin, and the transfer of these cells can correct β-thalassaemia in mouse models of the disease.

Prior to clinical trials in humans, the researchers wanted to ensure that this method of therapy was efficient and safe. In order to do this, they obtained bone marrow stem cells from 44 patients with β-thalassaemia major and analysed the properties of particular cells (progenitor HSC and CD34 cells) before and after transfer of the GLOBE vector. Properties such as frequency and site of integration of the gene were analysed, as well as its impact on the production of haemoglobin and the subsequent development of the cell.

Extensive analysis indicated that the vector was able to successfully be transferred into these cells and integrated into transcriptionally active regions, without bias for cancer-related genes. Inappropriate activation of such oncogenes by gene therapy vectors, causing cancer, has occurred before in such trials (see previous news).Integration of the vector restored synthesis of haemoglobin and did not appear to affect the subsequent development or the number of cells.

Comment: These pre-clinical trials are an initial step in the development of gene therapy for this disease, and may also provide a model for the use of gene therapy to treat other diseases such as sickle cell disease, for which the need to develop an effective therapy is pressing [Orkin and Higgs (2010) Science 329 (5989):291-292].

Children's Hospital Boston and Dana-Farber Cancer Institute, Harvard Medical School, Howard Hughes Medical Institute, Boston, MA 02115, USA. stuart_orkin@dfci.harvard.edu

PHG Foundation | Progress in gene therapy for beta-thalassaemia