IMPROVING SAFETY OF GENE TRANSFER

Retroviral vector (RV)-mediated gene transfer has an excellent therapeutic potential as demonstrated in recent clinical trials. A concurrent risk, however, is that RV integration in the host cellular genome may affect the function of cellular genes found at or near the insertion site, with deleterious consequences. Advanced-generation lentiviral vectors (LV) may provide several safety features not present in RV and alleviate such risk. In the first aim of this project, we will stringently and comparatively assess the potential toxicity of RV and LV. We have developed and validated experimental animal models and in vitro assays to assess vector toxicity. If our studies will indicate a low toxicity of LV, we will provide a major new rationale for advancing this vector system to clinical experimentation. We will also explore strategies to further improve the safety of LV, wherever the currently available versions stand in this respect. We will aim to improve vector design to reduce its impact on the function of genes flanking the integration site. Moreover, in a most ambitious attempt to entirely bypass the requirement for gene replacement and vector integration, we will develop new strategies allowing repair of inherited mutations at the endogenous locus.