Description du projet
Créer des «usines» de médicaments in situ pour l’administration de produits biothérapeutiques
Les produits thérapeutiques à base d’acides nucléiques représentent un traitement émergent pour répondre à des besoins médicaux insatisfaits, ciblant les maladies à l’échelle génétique en évitant l’expression des protéines qui les provoquent. L’une de leurs caractéristiques est qu’ils doivent être encapsulés dans des nanotransporteurs pour garantir leur stabilité et leur absorption efficace dans les cellules. Les vésicules extracellulaires (VE) s’avèrent prometteuses pour l’administration de médicaments, car elles bénéficient de la tolérance immunitaire en tant que nanoparticules natives et sont également capables de traverser des barrières biologiques, dont la barrière hématoencéphalique. Le projet DELIVER, financé par l’UE, vise à développer des nanotransporteurs synthétiques pour modifier de façon transitoire des cellules hépatiques in vivo et les transformer en «usines» productrices de VE spécifiques afin d’acheminer des produits biothérapeutiques vers des organes actuellement inaccessibles. L’objectif à long terme du projet est de créer une plateforme pour la modification de VE in situ, ce qui permettrait l’administration de pratiquement tout produit biothérapeutique.
Objectif
Nucleic acid-based medicines have opened a new avenue in drug discovery to target currently undruggable genes and to express therapeutic proteins, unlocking novel therapeutic options for a range of diseases, including neurodegeneration. However, they need to be encapsulated in nanocarriers to ensure their stability and efficient uptake into cells and tissues. Synthetic nanoparticles based on cell-penetrating peptides (CPPs) and, particularly, lipid nanoparticles (LNPs) have recently emerged as potent vectors for hepatic delivery. However, these systems fail to robustly target other organs in a safe manner.
Another promising nanocarrier for advanced drug delivery is extracellular vesicles (EVs) that have the ability to efficiently convey macromolecules into cells. As native nanoparticles, EVs benefit from immune tolerance as well as the ability to cross biological barriers to reach, for example, the brain. We have developed advanced strategies to bioengineer cells to generate EVs loaded with therapeutic RNAs and proteins. However, their production at scale is cumbersome and time consuming.
Here, I propose a platform development using synthetic nanocarriers to transiently engineer hepatic cells in vivo and harness EVs to functionally DELIVER biotherapeutics to currently unreachable, distant organs, focusing on brain. To achieve this, genetic constructs will be developed that allow for transient in situ engineering of cells in vivo and release of cargo (e.g. CRE)- laden EVs, displaying CNS-specific peptides, that can be functionally transported to distant organs, including brain. We will exploit the same strategy using CPP-based nanoformulations, recently developed in my lab, injected locally in brain to secrete EVs loaded with the disease-relevant protein GBA1 as a treatment strategy for Parkinson´s disease.
Long-term this novel project has enormous potential, as any engineered EV could be produced in situ and be used for delivery of virtually any biotherapeutics.
Champ scientifique
- medical and health sciencesbasic medicinepharmacology and pharmacydrug discovery
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesbiological sciencescell biology
- engineering and technologynanotechnologynano-materials
- medical and health sciencesbasic medicineneurologyparkinson
Programme(s)
Régime de financement
ERC-COG - Consolidator GrantInstitution d’accueil
17177 Stockholm
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