Development of a Small Interfering RNA that Reduces Production of Alpha-synuclein in Parkinson's Disease

Study Rationale: Parkinson’s disease (PD) is associated with a buildup of alpha-synuclein aggregates in the brain. Modulation of alpha-synuclein accumulation has been shown in multiple preclinical models to positively affect PD outcomes. Small interfering RNAs (siRNA) are a new class of drugs that display clinical efficacy for six to 12 months following a single administration. We describe further chemical optimization of a therapeutic siRNA that targets alpha-synuclein in the brain. We expect that with a single infusion in the cerebrospinal fluid, this drug would modulate alpha-synuclein expression throughout the brain for at least 6-12 months, providing a disease-modifying therapy for PD.

Hypothesis: We hypothesize that potent, safe, and long-lasting RNAi-based modulation of alpha-synuclein will result in a disease-modifying treatment for PD.

Study Design: After screening hundreds of compounds, we have identified a lead configuration that efficiently silences alpha-synuclein in cells and in animals. We will perform additional structure-activity relationship (SAR) optimization on the lead compound, including incorporating transformative innovative chemical modifications that will provide a tenfold enhancement of potency, safety and duration of effect. The compounds will be synthesized, tested in cells and then evaluated for their pharmacokinetic and pharmacodynamics profiles, adverse effects and the maximum tolerated dose in healthy animals and in preclinical models of PD.

Impact on Diagnosis/Treatment of Parkinson’s disease: We expect that the developed drug would be ready to move into formal preclinical evaluation and to generate a disease-modifying treatment for both early- and late-stage PD.

Next Steps for Development: The next step would be advancement toward formal application for investigational new drug (IND)-enabling studies, including good manufacturing practices and toxicology assessment. The results obtained from the current study should be sufficient to initiate a pre-IND discussion with FDA.