In vivo reprogramming of Extracellular Vesicles for Targeted Drug Delivery of genome editors to the Central Nervous System
This project is part of the Therapeutic Genomics Centre, a multidisciplinary programme of innovative approaches to treating rare genetic disorders and providing an enhanced training experience for DPhil applicants.
Academic Supervisors: Prof. Matthew P.A Wood, Prof. Stephen Hyde
Other Supervisors: Dr. Dhanu Gupta
Host Dept: Paediatrics, Oxford
Delivery of CRISPR reagents to the brain represents a significant opportunity to unlock treatments for hundreds of rare neurological diseases. However, existing viral delivery methods suffer from major shortcomings in toxicity and efficacy. To address these challenges, we propose a novel approach that combines advances in synthetic delivery tools with exosome-based delivery systems.
Our strategy involves utilizing state-of-the-art synthetic vectors, specifically lipid nanoparticles (LNPs), to target a subset of cells in the brain. These cells will be transiently engineered with modified mRNA to function as biofactories, secreting extracellular vesicles (EVs) encapsulating CRISPR ribonucleoproteins. These exosomes can then target a broader range of neurons in the central nervous system, achieving more effective delivery with reduced toxicity. To advance this approach toward clinical application, we will employ a unique, novel ex vivo human brain model. This model will allow us to target various neuronal populations, refining our delivery system into a cutting-edge tool for CRISPR-based therapies.
This innovative strategy aligns with the Therapeutic Genomics Centre’s focus on developing advanced delivery tools to address the unmet clinical needs in neurological disorders. By integrating leading-edge bioengineering techniques, we aim to create a versatile platform for precise therapeutic interventions in neurological diseases. This approach holds the potential to overcome current limitations in drug delivery, offering a new pathway to treat complex conditions with high specificity, minimal side effects, and a clear plan for clinical translation using our novel ex vivo human brain model.
Studentship code: MRCTGCORE2024006
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