Development of a lentiviral vector for gene therapy of ADA deficiency

ADA deficiency is a severe form of immunodeficiency which leaves affected children very vulnerable to infections from all types of bacteria and viruses. Bone marrow transplant can correct the disease but carries with it major difficulties especially if a fuly matched donor is not available. For this reason, attempts to cure the disease by gene therapy have been developed. In initial trials, this has been very promising but the current methods by which the ADA gene is introduced into the child s cells may have potential problems for the future. We are now trying to develop safer ways of carrying genes into cells and in this project we aim to test whether these new methods are both effective and safe.

Adenosine deaminase (ADA) deficiency leads to severe combined immunodeficiency resulting in recurrent infections and death in the first year of life without definitive treatment. Gene therapy using gammaretroviral vector mediated correction of autologous haematopoietic stem cells (HSCs) has shown significant efficacy in correcting the immunological defects associated with ADA deficiency. However, the use of gammaretroviral vectors is complicated by their potential for insertional mutagenesis which has led to the development of leukaemia in patients treated by gene therapy for other immunodeficiencies. There is a pressing need to move to safer but equally efficacious vector strategies. Lentiviral vectors are able to transduce HSCs effectively but exhibit a significantly reduced potential for insertional mutagenesis. We have generated lentiviral vectors with the ADA gene under the transcriptional control of an internal mammalian promoter. We aim to demonstrate the efficacy and safety of this lentiviral vector in promoting immune and metabolic correction in cellular and animal models of ADA deficiency. These studies are critical before such vectors can be used in clinical studies.