Study Rationale: Alpha-synuclein (SNCA) aggregation is a hallmark of Parkinson’s disease (PD). Rare SNCA genetic duplications and triplications cause early-onset PD, suggesting a link between SNCA dose and disease risk. Genome-wide association studies (GWAS) have consistently identified SNCA as the strongest common genetic risk factor for idiopathic PD. However, the molecular mechanism linking SNCA variants to disease progression has remained unclear.
Our work has revealed that a specific SNCA transcript isoform (dIRE-SNCA) is strongly associated with PD risk and progression. This dIRE-SNCA isoform is preferentially expressed in vulnerable dopaminergic neurons, correlates with worse motor and cognitive outcomes, and accelerates disease progression. Based on these findings, we propose to develop a splice isoform-selective antisense oligonucleotide (ASO) therapeutic to selectively suppress dIRE-SNCA. This precision-medicine approach directly targets a disease-driving mechanism while reducing the risk of off-target effects.
Hypothesis: We hypothesize that increased expression of the disease-associated dIRE-SNCA transcript drives PD progression by promoting excessive alpha-synuclein accumulation, neuronal dysfunction, and neurodegeneration. Selectively lowering dIRE-SNCA levels while preserving the normal isoform will slow disease progression and improve patient outcomes.
Study Design: We will develop and optimize an ASO therapeutic that selectively targets dIRE-SNCA, thereby reducing disease-driving alpha-synuclein production while preserving essential physiological functions of SNCA. The study consists of three key aims:
- Lead Optimization: Design and optimize ASOs that selectively knock down dIRE-SNCA.
- Preclinical Validation: We will evaluate ASO-mediated knockdown of dIRE-SNCA in humanized SNCA mouse models and assess effects on α-synuclein mRNA levels, protein levels, aggregation, neuronal function, and disease progression markers.
- Clinical Biomarker & Patient Selection Strategy: We will use longitudinal clinical data from PPMI to define thresholds of dIRE-SNCA expression linked to rapid disease progression and establish a patient selection framework to identify those PD patients most likely to benefit from our therapy.
Impact on Diagnosis/Treatment of Parkinson’s disease: If successful, this approach will enable the first selective therapy for PD, addressing a genetically validated and clinically predictive driver of disease progression, SNCA. Based on our genetics work, this strategy has the potential to: Slow motor and cognitive decline in PD patients and avoid the risks of total SNCA knockdown, which may cause anemia and/or unintended effects on neuronal function. By directly targeting a disease-driving molecular signature, this therapy could transform the treatment landscape for PD, and the safety of this approach could unlock peripheral dosing strategies that would dramatically improve the patient experience.
Next Steps for Development: Upon successful completion of this study, we will be positioned to: advance lead molecules into IND-enabling studies, validate dIRE-SNCA biomarkers for use in clinical trials, and engage with regulatory agencies to establish a path for first-in-human trials targeting a genetically and clinically defined patient population.