UNDERSTANDING THE INTERACTIONS BETWEEN RETROVIRAL GENE TRANSFER VECTORS AND THE HUMAN GENOME

Retroviral vectors are the most efficient tools to transfer genes into human cells for gene therapy of genetic diseases. The use of these vectors, however, has raised safety concerns for the risk associated to their uncontrolled insertion into the human genome. The occurrence of leukemia in patients treated by gene therapy for a rare form of inherited immunodeficiency in France has been correlated with the activation of an oncogene in the patients’ cells by the therapeutic vector. Our poor understanding of these deleterious interactions between viral vectors and the human genome is a serious obstacle to the development of safe and efficient gene transfer technology, and in general to the development of gene therapy as an effective medical intervention. The aim of this project is to study the molecular mechanisms underlying the integration preferences of retroviral vectors, and the role of vector design in influencing integration into the genome and perturbation of gene expression. The study will directly address the issue of vector safety, and provide knowledge, tools, and assays to tailor the choice and design of gene transfer vectors for human hematopoietic and epidermal stem cells. These cells are the target of ongoing or planned gene therapy trials for severe monogenic diseases, such as immunodeficiencies, lysosomal storage disorders, thalassemia and skin adhesion defects.