Development of an enhanced lentiviral vector for gene therapy of ADA-SCID

Adenosine deaminase deficiency is a condition in which affected children lack a functional immune system and die from infection in the first year of life. The nature of the gene defect is such that severe defects are also found in other systems of the body. Due to the limitations of other treatment options, gene therapy has recently been used with some success in correcting the immune defects. In this study we hope to build on this and test better gene therapy delivery vectors that may correct both the immune system and non-immune system problems. We will also use vectors that have improved safety profiles compared to presently used constructs. We will test our new vectors in cellular systems and also aim to correct a murine model of the disease.

Somatic gene therapy has long been held as a major goal for correction of monogenic diseases. The promise of over two decades of basic and pre-clinical research has now been realised with the demonstration of significant therapeutic effect in clinical studies on a number of severe congenital immunodeficiencies including SCID-X1 (X-linked severe combined immunodeficiency), ADA-SCID (adenosine deaminase deficient SCID) and X-CGD (X-linked chronic granulomatous disease). To date, successful gene transfer has been mediated by conventional gammaretroviral vectors which show efficient and stable integration into haematopoietic stem cells (HSC) but have also demonstrated the potential for significant side effects through inadvertent gene activation. For ADA-SCID, where the ADA gene is expressed in all somatic tissues and where clinically defects exist outside of the immune system, systemic gene delivery may have added therapeutic benefit. In this application, we aim to build on our highly promising phase I/II gene therapy trials for ADA-SCID and to develop and test vectors with improved safety profiles and enhanced ADA gene delivery. We plan to develop lentiviral vectors in which the ADA gene is transcribed from a non-viral promoter which is also under the influence of the beta-globin locus control region (LCR). Using this construct, we hope to achieve high level expression in lymphocytes to allow T and B cell development, but also beta-globin LCR driven expression in erythrocytes which may allow for greater systemic ADA expression and provide better metabolite detoxification. The use of a lentiviral construct with deleted long terminal repeat sequences and an internal promoter will also provide an improved safety profile.