Human SNCA Antisense Oligonucleotides Reduce CNS and CSF Alpha-Synuclein Levels in a Non-Human Primate Model Supporting Their Use for Treatment of Synucleinopathies
Tracy Cole1, Eric Swayze1, Danielle Graham2, Andreas Weihofen2, Luke Jandreski2, Warren Hirst2, Miroslaw Brys2, Roger Lane1, Frank Bennett1, Jesse M. Cedarbaum2, Holly Kordasiewicz1
1Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA, 2Biogen, Cambridge, MA, USA
The objective was to investigate the effect of human alpha-synuclein (SNCA gene) antisense oligonucleotides on RNA and protein reduction in the non-human primate in the CNS and evaluate the potential to use alpha-synuclein levels in the CSF as a pharmacodynamic (target engagement) biomarker. Parkinson's disease (PD) is a prevalent neurodegenerative disease for which there are no approved disease-modifying therapies. Alpha synuclein accumulation is a pathological hallmark of PD and other synucleinopathies, such as Multiple System Atrophy (MSA). Multiplication of the alpha synuclein gene, SNCA, alone can result in PD. Antisense oligonucleotides designed to target SNCA RNA result in reduced production of alpha synuclein and thus have the potential to slow spread of pathology and modulate disease progression. Human targeting SNCA ASOs (NHP homologous) were administered centrally to NHPs following which brain tissue and CSF were evaluated for alpha-synuclein reduction. Following study completion SNCA RNA was evaluated by RT-PCR and alpha synuclein protein was evaluated by ELISA and histologically. Human SNCA targeting antisense oligonucleotides led to SNCA RNA and protein reduction throughout the brain and spinal cord. Brain tissue protein levels of alpha-synuclein were correlated with CSF levels supporting the use of alpha-synuclein protein levels in the CSF as a target engagement biomarker. Thus, human antisense oligonucleotides designed against SNCA have the potential to be a disease modifying therapeutic for patients with synucleinopathies and are currently moving toward the clinic.