Description du projet
Un nouveau virus synthétique pour l’administration ciblée de gènes
La capacité des virus à infecter, pénétrer et se répliquer dans les cellules a suscité un grand intérêt dans le domaine de la thérapie génique. Le projet GENESHUTTLE, financé par l’UE, entend créer des structures synthétiques semblables à des virus, qui transportent des informations génétiques intéressantes et reproduisent les propriétés des virus naturels. Les chercheurs utiliseront la technique de l’origami ADN pour garantir un repliement correct des acides nucléiques, tandis que les particules générées seront capables d’interagir avec les membranes cibles, de déclencher l’internalisation tout en évitant une réplication autonome incontrôlée. Le système d’administration GENESHUTTLE constituera une avancée significative par rapport aux approches actuelles et devrait trouver des applications immédiates dans la recherche et la médecine.
Objectif
Using rational design with DNA origami, we propose to create synthetic virus-like assemblies capable of accomplishing cell-invading and gene expression functionalities known so far only from natural viruses. We envision these assemblies to be useful for studying and testing viral import mechanisms, and also for gene delivery, enabling fundamental studies and potential medical applications. The objectives include selecting and invading a target cell type, systematically solving the challenges of endosomal escape and nuclear delivery, and inducing the expression of user-defined genetic information in the nucleus. To achieve these objectives, we will recreate and experimentally test mechanisms believed to be used by viruses, including receptor-mediated endocytosis, stimulus-dependent lipid membrane penetration, membrane fusion, active cytosolic transport, and nuclear import. We foresee building synthetic shells carrying genetic information stored in nucleic acids, which we refer to as the “gene shuttle”. The particles will optionally include a membrane envelope and user-defined surface features to mediate receptor-ligand interactions with cell membranes, and they will be capable of stimulus-dependent conformational changes to trigger membrane fusion or membrane penetration. They will shed structural elements on the path to the nucleus, similar to viruses. In addition to delivering genes for fluorescent markers, as a proof of concept demonstration we plan to use the gene shuttle to deliver the genetic information for expressing chimeric antigen receptors (CAR) in a T cell line, which promises to be of use in cancer immunotherapy. The project promises to yield a gene delivery system with capabilities beyond current synthetic vectors, which struggle to overcome the many cellular barriers to deliver and express genetic cargo. For safety reasons, the gene shuttle will by design be unable to assemble in the context of a cell to prevent uncontrolled autonomous replication.
Champ scientifique
- natural sciencesbiological sciencesbiochemistrybiomoleculesnucleic acids
- natural sciencesbiological sciencesmicrobiologyvirology
- natural sciencesbiological sciencesbiochemistrybiomoleculeslipids
- medical and health sciencesclinical medicineoncology
- medical and health sciencesbasic medicineimmunologyimmunotherapy
Mots‑clés
Programme(s)
Thème(s)
Régime de financement
ERC-ADG - Advanced GrantInstitution d’accueil
80333 Muenchen
Allemagne