PERSIST Project

PERSIST stands for "Persisting Transgenesis". This is a Large Scale Integrated Project in the FP7 Health theme that addresses the development of emerging gene therapy tools and technologies for clinical application. The project coordinator is Prof. Luigi Naldini, from Vita-Salute San Raffaele University of Milan. PERSIST started on 1st January 2009 and will run four years until 31st December 2012.

For many disabling or fatal diseases, there is pre-clinical or clinical evidence of the potential therapeutic efficacy of gene therapy, especially in the areas of inherited immune and enzyme deficiencies. However, current gene transfer technologies have inherent limitations and may result in undesirable mutagenic effects. PERSIST explores the use of highly innovative gene-modifying and delivery technologies and capitalizes on recent discoveries in gene expression control to develop radical solutions to precisely controlling the fate and expression of exogenous genetic information in gene therapy, with applications in these and other deadly diseases. The project combines 22 of Europe's outstanding experts from 11 countries in the field of genetic engineering for persisting gene expression. Target diseases focus on inherited immune deficiencies, lysosomal storage disorders and haemophilias.

To achieve these objectives, the research programme of PERSIST is organised in several Work Packages (WP) as shown in the figure below representing the scientific approach of the project.

The PERSIST project has four main goals which are strategic for innovative technology developemnt in the field of genetic engineering for persisting gene expression:                                                                                                                                - Long-term gene transfer without adverse effect on the host chromatin, including stable non-integrative gene transfer and targeted integration without impact on endogenous gene transcription,                                                                                                     - Site-specific genome modification, allowing a range of approaches such as gene correction, gene targeting and site-specific gene addition,                                                                                                                                                                                 - Tight control on target cell selection or immune recognition by engineering the vector particle,                                                      - Tight control of transgene expression exploiting recent discoveries on gene expression control, such as microRNA, on chromatin structure and organisation, and designer transcriptional switches.

These strategic goals provide the vertical R&D axes of the project and are addressed in WPs 1-6. They will provide new strategies to establish long-term transgene expression and concurrently alleviating the risk of inducing immune responses, transgene toxicity (phenotoxicity) and genotoxicity.

Besides, the horizontal R&D axes of PERSIST are on applications and evaluation. Most importantly, the overall goal of PERSIST is the application of the new gene therapy strategies being developed to the definition of safe and effective gene therapy protocols for severe human diseases. Three disease families have been selected (WPs 10-12) for the urgent need of improved gene transfer strategies and the potential for successful response and long-term cure: X-linked severe combined immunodeficiency (SCIDX1), Lysosomal storage diseases and Hemophilias. These diseases chosen by PERSIST represent crucial paradigms for novel therapeutic options that can be explored by genetic modification of several important cellular targets (WPs 8-9): Hematopoietic Stem Cells (HSCs), Lymphocytes, Mesenchymal Stem Cells (MSCs), hepatocytes, and induced Pluripotent Stem Cells (iPSCs).

These R&D activities are complemented with WP7 on biosafety studies, WP13 on bioprocess development, WP14 on ethics and regulatory issues, and WP15 dealing with training and dissemination activities.