Descrizione del progetto
Creare «fabbriche» di farmaci in situ per la somministrazione di bioterapie
Le terapie a base di acido nucleico rappresentano un trattamento emergente per le esigenze mediche non soddisfatte, intervenendo su malattie a livello genetico impedendo l’espressione di proteine che provocano la malattia stessa. Una delle loro caratteristiche consiste nel fatto che hanno bisogno di essere incapsulate in nanovettori per garantire stabilità e l’assorbimento efficiente nelle cellule. Un nanovettore promettente per la somministrazione di farmaci è rappresentato dalle vescicole extracellulari, che traggono vantaggio dalla tolleranza immunitaria in quanto nanoparticelle native, oltre a essere anche in grado di attraversare barriere biologiche, quali la barriera ematoencefalica. Il progetto DELIVER, finanziato dall’UE, si propone di sviluppare nanovettori sintetici per ingegnerizzare temporaneamente cellule epatiche in vivo e trasformarle in «fabbriche» specifiche che producono tali vescicole volte a fornire bioterapie agli organi attualmente irraggiungibili. L’obiettivo a lungo termine del progetto è quello di creare una piattaforma per la progettazione di vescicole extracellulari in situ, consentendo la somministrazione di pressoché qualsiasi prodotto bioterapeutico.
Obiettivo
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.
Campo scientifico
- medical and health sciencesbasic medicinepharmacology and pharmacydrug discovery
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesbiological sciencescell biology
- engineering and technologynanotechnologynano-materials
- medical and health sciencesbasic medicineneurologyparkinson
Parole chiave
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-COG - Consolidator GrantIstituzione ospitante
17177 Stockholm
Svezia