In vivo Target Validation: RNA Interference to Silence Alpha-Synuclein in Parkinson’s Disease Pre-clinical Models

Recent studies have shown that a protein known as alpha-synuclein plays a central role in the development of Parkinson’s disease. While its normal function in the brain remains unknown, the accumulation of excess alpha-synuclein has been shown to be the cause of familial forms of PD. It now appears that accumulation of alpha-synuclein in neurons is a key feature of non-inherited PD as well. Therefore, it has been hypothesized that reducing the levels of alpha-synuclein in the brain of PD patients may slow the progression of the disease and, perhaps, even relieve symptoms.

To date, no drugs have been identified that are capable of lowering alpha-synuclein levels in the brain, thus new approaches are needed. “RNA interference” (RNAi) is a natural mechanism present in all cells whereby small, double-stranded RNA molecules known as “short interfering RNAs” (siRNAs) specifically silence gene expression by the targeted destruction of messenger RNA, the molecule that contains the instructions for protein synthesis.

We propose to test the ability of siRNAs targeted against alpha-synuclein to reduce alpha-synuclein levels in the brains of rodents. The siRNAs are chemically modified to enhance their stability in tissues, and to improve cellular uptake. By delivering the siRNAs directly into the brains of rodents genetically engineered to express excess alpha-synuclein protein, we will be able to assess their effects on the development of PD-like symptoms over time. Success in these studies could pave the way for novel treatments of PD based on infusion of siRNAs into the brains of Parkinson’s patients.