Abstract
Parkinson’s disease (PD) is a prevalent neurodegenerative disease with no approved disease-modifying therapies. Multiplications, mutations, and single nucleotide polymorphisms in the SNCA 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 SNCA targeting ASOs that efficiently suppress the human SNCA transcript in vivo. We demonstrate broad activity and distribution of the human SNCA 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 SNCA ASOs as a potentially disease modifying therapy for PD and related synucleinopathies.
Summary Antisense oligonucleotides designed against SNCA, which are progressing to the clinic, have the potential to be a disease modifying therapeutic for Parkinson’s disease patients.
Abbreviations
- PD
- Parkinson’s disease
- CNS
- central nervous system
- mRNA
- mature ribonucleic acid
- Snca/SNCA
- alpha synuclein rodent/human gene, respectively
- aSyn
- alpha synuclein protein
- LB
- Lewy body
- LN
- Lewy neurite
- ASO
- antisense oligonucleotide
- PFF
- pre-formed fibril
- CSF
- cerebrospinal fluid
- NHP
- non-human primate
- MSA
- multiple systems atrophy
- DLBD
- Diffuse Lewy body disease
- GD
- Gaucher disease
- PAF
- pure autonomic failure
- TH+
- tyrosine hydroxylase positive
- DA
- dopamine
- SN
- substantia nigra
- IHC
- immunohistochemistry
- pSer129+ aggregates
- phospho serine 129 positive aggregates