Alpha-synuclein antisense oligonucleotides as a disease-modifying therapy for Parkinson’s disease

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