Clinical trial of self-inactivating vectors for gene therapy of X-linked Severe Combined Immunodeficiency (SCID-X1)

Gene therapy has the potential to treat a wide range of inherited diseases. Recently, several trials have shown that children with defects of their immune system (often called bubble babies because they are kept in germ free rooms) can be successfully treated in this way by putting new genes into the blood-making factory called bone marrow. However, the way in which the new genes are transplanted into the bone marrow, using modified viruses or vectors, has also been shown in a few children to have unfortunate side-effects. We now know that these arise because the vectors inadvertantly activate other genes that keep the cells in our body healthy. In the worst case, this can cause cancer. However, we also now believe that the risk of this occuring can be substantially limited by improved design of the vectors themselves. Following on from highly encouraging experiments in the laboratory, we would now like to test this strategy in patients for whom coventional bone marrow transplantation is difficult. This will not only provide a new treatment for patients with immune defects, but will provide a platform on which gene therapy can be safely developed for many other diseases.

Somatic gene therapy has been proposed as an exciting new therapeutic strategy for treatment of human genetic disease. Four recent studies have demonstrated highly effective gene therapy for the X-linked form of severe combined immunodeficiency (SCID-X1) and ADA-deficiency, using mammalian retroviruses to deliver the therapeutic genes into haematopoietic stem cells ex vivo. SCID-X1, caused by mutations in the common cytokine receptor gamma chain (gamma-c), is invariably fatal in the absence of therapeutic bone marrow transplantation. In the presence of HLA-matched family donors, the majority of patients can expect to be cured. For other donor sources, particularly parental, success rates are reduced, and full restoration of immunity is often not achieved. We have recently successfully treated seven children with molecularly defined SCID-X1 by gene transfer to bone marrow CD34+ cells using a gibbon ape leukaemia virus (GALV)-pseudotyped gammaretroviral vector. However, the development of leukaemia in patients enrolled in a similar trial has highlighted the risk of inadvertent gene activation through insertional mutagenesis. We have therefore explored strategies to minimise this risk by development of gammaretroviral vectors that are deleted for powerful endogenous viral enhancer sequences (SIN). We are currently in the final phases of testing these vectors, but have shown that they retain the capacity for correction of the SCID-X1 disease phenotype in animal models, and have a significantly reduced mutagenic potential in vitro. Here we propose a clinical trial for testing these novel vectors in human patients. This will be the first clinical study using SIN gammaretroviral technology, and will hopefully establish a solid platform for the development of safe and efficacious gene therapy in many other disease types.