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ANTISENSE OLIGONUCLEOTIDES TARGETING SNCA REDUCE ALPHA-SYNUCLEIN AND ASSOCIATED CELLULAR PATHOLOGY IN PARKINSON’S PATIENT IPSC-DERIVED MIDBRAIN DOPAMINERGIC NEURONS
Abstract
Aims
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder and the fastest growing neurological disease. With no approved curative or disease-modifying therapies available, PD presents a major unmet clinical need. Overwhelming evidence suggests the abnormal aggregation of the protein α-synuclein, encoded by the SNCA gene, is the causative agent of PD. Multiplications of the SNCA gene are known to cause familial PD, whilst PD risk loci identified through genome-wide association studies have been shown to regulate SNCA expression. Here, we aim to validate a SNCA-targeting antisense oligonucleotide (ASO) approach in a human model system of PD.
Methods
We use targeted long-read RNA sequencing of SNCA to reveal the transcriptional landscape of the SNCA gene in midbrain dopaminergic (mDA) neurons generated from PD patient-derived induced pluripotent stem cells. We then use novel antisense oligonucleotides (ASOs) targeted to SNCA to examine the effect of reduced α-synuclein expression on cellular pathology.
Results
In these neurons, we find a number of novel SNCA isoforms, including those with alternative 5′ start sites and variable 3′ UTR lengths, and we show that relative transcript expression of isoforms differs across genotypes. Importantly, we demonstrate that an SNCA-targeting ASO-induced reduction in α-synuclein expression reverses established α-synuclein pathology and rescues cell death in these neurons. We further demonstrate that this improvement in neuronal health may be mediated through an amelioration of mitochondrial function.
Conclusions
In summary, our data supports the continued exploration of ASO technology targeted to SNCA as a novel disease-modifying therapy for PD and other related synucleinopathies.