Platform development of engineered extracellular vesicles for gene editing in the CNS

To date, there are no curative treatments for most neurodegenerative disorders, including synucleinopathies of the central nervous system (CNS) such as Parkinsons disease (PD).

The greatest challenges in treating these are currently insufficient penetration of drugs to the parenchyma of the brain and achieving stable reduction of α-synuclein (SNCA) protein aggregation, the most significant hallmark of PD pathology. Therefore, it is imperative to find new solutions to these unmet medical needs.

Recently, we have harnessed nature’s own nanoparticles, extracellular vesicles (EVs), for targeted delivery of biotherpeutics, with focus on Cas9-based gene editors.

Here, we will establish a novel CNS delivery platform exploiting these engineered EVs for CRISPR/Cas9-mediated silencing of SNCA gene expression and prevention of α-synuclein aggregation.

After optimization of EV engineering components focusing on enhanced cargo loading, gene editing, and EV delivery to deep brain parenchyma, we will demonstrate their therapeutic effect in models of PD by local injection into the brain of mice using osmotic pumps. If successful, this will open an entirely new avenue to treat PD and other synucleinopathies.

Importantly, the modular nature of the EV engineering platform permits further adaptation to deliver other gene editors or drug modalities, thereby opening innovative possibilities to treat a range of CNS diseases.