α-Synuclein antisense oligonucleotides as a disease-modifying therapy for Parkinson’s disease

• DOI: 10.1172/jci.insight.135633
• Publication Date: 2021-03-07T19:01:15Z
• Authors: Tracy A. Cole; Hien Zhao; Timothy J. Collier; Ivette Sandoval; Caryl E. Sortwell; Kathy Steece-Collier; Brian F. Daley; Alix Booms; Jack Lipton; Mackenzie Welch; Melissa Berman; Luke Jandreski; Danielle Graham; Andreas Weihofen; Stephanie Celano; Emily Schulz; Allyson Cole-Strauss; Esteban Luna; Duc Quach; Apoorva Mohan; C. Frank Bennett; Eric E. Swayze; Holly B. Kordasie...; Kelvin C. Luk; Katrina L. Paumier
• Keywords: Synucleinopathies; Antisense therapy

Parkinson's disease (PD) is a prevalent neurodegenerative with no approved disease-modifying therapies. Multiplications, mutations, and single nucleotide polymorphisms in the SNCA gene, encoding α-synuclein (aSyn) protein, either cause or increase risk for PD. Intracellular accumulations of aSyn are pathological hallmarks Taken together, reduction production may provide therapy We show that antisense oligonucleotides (ASOs) reduce rodent preformed fibril (PFF) models Reduced leads to prevention removal established pathology prevents dopaminergic cell dysfunction. In addition, we address translational potential approach through characterization human SNCA-targeting ASOs efficiently suppress transcript vivo. demonstrate broad activity distribution throughout nonhuman primate brain corresponding decrease cerebral spinal fluid (CSF) levels. these data suggest that, by inhibiting aSyn, it be possible reverse pathology; thus, support development as PD related synucleinopathies.