Descripción del proyecto
Creación de «fábricas» de fármacos «in situ» para la administración de biofármacos
Los fármacos basados en ácidos nucleicos constituyen un tratamiento de nueva aparición para las necesidades médicas insatisfechas, ya que permiten tratar una enfermedad a nivel genético al impedir la expresión de proteínas que la causan. Una de sus características es que deben encapsularse en nanotransportadores para garantizar su estabilidad y su absorción eficaz en las células. Las vesículas extracelulares (VE) constituyen un nanotransportador prometedor para la administración de fármacos, ya que presentan una tolerancia inmunitaria similar a la de las nanopartículas nativas y pueden atravesar barreras biológicas como, por ejemplo, la barrera hematoencefálica. El proyecto DELIVER, financiado con fondos europeos, se propone desarrollar nanotransportadores sintéticos para modificar de forma temporal hepatocitos «in vivo» y convertirlos en «fábricas» específicas de producción de VE para administrar biofármacos a órganos actualmente inalcanzables. Su objetivo a largo plazo es crear una plataforma de ingeniería de VE «in situ» que permita la entrega de prácticamente cualquier biofármaco.
Objetivo
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.
Ámbito científico
- medical and health sciencesbasic medicinepharmacology and pharmacydrug discovery
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesbiological sciencescell biology
- engineering and technologynanotechnologynano-materials
- medical and health sciencesbasic medicineneurologyparkinson
Palabras clave
Programa(s)
Régimen de financiación
ERC-COG - Consolidator GrantInstitución de acogida
17177 Stockholm
Suecia