Descripción del proyecto
Un nuevo virus sintético para una administración selectiva de genes
La capacidad de los virus de infectar, penetrar y replicar las células ha captado un gran interés en el ámbito de la terapia génica. El objetivo del proyecto GENESHUTTLE, financiado con fondos europeos, es crear estructuras sintéticas similares a los virus que transporten información genética relevante y sinteticen las propiedades de los virus naturales. Los investigadores emplearán la técnica del origami de ADN para garantizar un plegado correcto de los ácidos nucleicos, mientras que las partículas generadas serán capaces de interactuar con membranas diana y desencadenar la internalización, pero evitando una replicación autónoma descontrolada. El sistema de administración de GENESHUTTLE constituirá un gran progreso respecto a los métodos actuales y podrá aplicarse de forma inmediata en la investigación y la medicina.
Objetivo
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.
Ámbito científico
- natural sciencesbiological sciencesbiochemistrybiomoleculesnucleic acids
- natural sciencesbiological sciencesmicrobiologyvirology
- natural sciencesbiological sciencesbiochemistrybiomoleculeslipids
- medical and health sciencesclinical medicineoncology
- medical and health sciencesbasic medicineimmunologyimmunotherapy
Palabras clave
Programa(s)
Régimen de financiación
ERC-ADG - Advanced GrantInstitución de acogida
80333 Muenchen
Alemania