Exosome-mediated delivery of antisense oligonucleotides targeting alpha-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 alpha-synuclein (alpha-syn). The aberrant aggregation of alpha-syn is believed to play a key role in the pathogenesis of PD. While alpha-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 alpha-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 alpha-syn aggregation induced by pre formed alpha-syn fibrils in vitro. Exo-ASO4 intracerebroventricular injection into the brains of alpha-syn A53T mice, a transgenic model of PD, significantly decreased the expression of alpha-syn and attenuated its aggregation. Furthermore, exo-ASO4 ameliorated the degeneration of dopaminergic neurons in these mice. Finally, the alpha-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.

Automated summary

This study demonstrated that exosome-mediated delivery of ASO4 could effectively reduce alpha-synuclein expression, attenuate its aggregation, and improve locomotor functions in a transgenic model of Parkinson's disease.