Project description
Creating in situ drug "factories" for the delivery of biotherapeutics
Nucleic acid therapeutics represent an emerging treatment for unmet medical needs, targeting disease at the genetic level by preventing the expression of disease-causing proteins. One of their characteristics is that they need to be encapsulated in nanocarriers to ensure stability and efficient uptake into cells. A promising nanocarrier for drug delivery is extracellular vesicles (EV), which benefit from immune tolerance as native nanoparticles, and they are also able to cross biological barriers, including the blood–brain barrier. The EU-funded DELIVER project aims to develop synthetic nanocarriers to transiently engineer hepatic cells in vivo and turn them into specific EV-producing "factories" to deliver biotherapeutics to currently unreachable organs. The long-term project goal is to create a platform for in situ EV engineering, enabling the delivery of virtually any biotherapeutic product.
Objective
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.
Fields of science
- 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)
Funding Scheme
ERC-COG - Consolidator GrantHost institution
17177 Stockholm
Sweden