Objective/Rationale:
Clinical, genetic and experimental evidence supports an association between alpha-synuclein expression and Parkinson’s disease. This toxicity is likely to be attenuated by strategies that result in a decrease in alpha-synuclein levels. We will develop ‘small interfering RNA’ (siRNA)-based therapeutics to lower alpha-synuclein expression with the ultimate goal of identifying molecules and delivery systems suitable for clinical application in patients.
Project Description:
Preliminary work in our laboratories has demonstrated that siRNA is potent at reducing alpha-synuclein expression in pre-clinical models, and supports the use of siRNA-based therapeutics in PD. In this project we plan to: 1) design and produce potent siRNAs, chemically modified to prevent degradation and inflammation and to facilitate their diffusion through the brain parenchyma; 2) test siRNAs capable of reducing alpha-synuclein expression in models; 3) evaluate the effectiveness of siRNA in counteracting alpha-synuclein pathology and neuronal injury in these models; and 4) optimize siRNA/vehicle formulations and delivery methods, leading to Phase I clinical trials.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Our work will help define the role of alpha-synuclein expression in the pathological process while developing siRNA technology as an effective and safe therapeutic approach for PD.
Anticipated Outcome:
Therapeutics based on siRNA represent an entirely new class of drugs with the potential to address traditionally “undruggable” targets, such as alpha-synuclein. As a proof of concept, we have generated preliminary data showing that alpha-synuclein siRNA infused directly into model brain specifically reduces gene and protein expression. We plan to identify the optimal alpha-synuclein siRNA drug candidate, establish efficacy and the “therapeutic window” for brain infusion in models, and ultimately determine safety of siRNA infusion in patients with PD. Furthermore, results of these multicenter studies will yield important mechanistic data on the relationship between alpha-synuclein expression, the development of alpha-synuclein pathology (e.g. Lewy body formation) and neurodegeneration.