Exosome-mediated delivery of antisense oligonucleotides targeting α-synuclein ameliorates the pathology in a mouse model of Parkinson's disease

Parkinson's disease (PD) is the second most common neurodegenerative disease. Pathologically, PD is characterized by the formation of Lewy bodies (LBs) in the brain, which mainly comprises phosphorylated and aggregated α-synuclein (α-syn). The aberrant aggregation of α-syn is believed to play a key role in the pathogenesis of PD. While α-syn expression can be reduced by antisense oligonucleotides (ASOs), the challenge to deliver ASOs safely and effectively into the neurons remains unresolved. Here, we developed a safe and highly effective ASO delivery method by using exosomes. We first identified the ASO sequence that selectively reduced α-syn expression: ASO4. Exosome-mediated delivery of ASO4 (exo-ASO4) showed high cellular uptake and low toxicity in primary neuronal cultures. Exo-ASO4 also significantly attenuated α-syn aggregation induced by pre-formed α-syn fibrils in vitro. Exo-ASO4 intracerebroventricular injection into the brains of α-syn A53T mice, a transgenic model of PD, significantly decreased the expression of α-syn and attenuated its aggregation. Furthermore, exo-ASO4 ameliorated the degeneration of dopaminergic neurons in these mice. Finally, the α-syn A53T mice showed significantly improved locomotor functions after exo-ASO4 injection. Overall, this study demonstrates that exosome-mediated ASO4 delivery may be an effective treatment option for PD. •Exosomes are suitable carrier for the ASO delivery into the mouse neurons.•Exosome-mediated ASO4 delivery (exo-ASO4) can both reduce the expression level of α-synuclein and phosphorylated α-synuclein.•Exo-ASO4 attenuates α-syn pathology and thereby improves motor function in the α-syn A53T mice.•Exo-ASO4 may be an effective treatment option for PD.