Methodology

In vivo silencing of alpha-synuclein using naked siRNA

Jada Lewis^1* , Heather Melrose^1* , David Bumcrot² , Andrew Hope^1,5 , Cynthia Zehr¹ , Sarah Lincoln¹ , Adam Braithwaite¹ , Zhen He¹ , Sina Ogholikhan¹ , Kelly Hinkle¹ , Caroline Kent¹ , Ivanka Toudjarska² , Klaus Charisse² , Ravi Braich² , Rajendra K Pandey² , Michael Heckman³ , Demetrius M Maraganore⁴ , Julia Crook³ and Matthew J Farrer¹

¹  Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA

²  Alnylam Pharmaceuticals, 300 3rd St, Cambridge, MA 02142, USA

³  Department of Biostatistics, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA

⁴  Department of Neurology, Mayo Clinic, 200 1st St SW, Rochester, MN 55905, USA

⁵  ReNeuron, 10 Nugent Road, Surrey Research Park, Guildford, Surrey, GU2 7AF, UK

author email corresponding author email* Contributed equally

Molecular Neurodegeneration 2008, 3:19doi:10.1186/1750-1326-3-19

Published:	1 November 2008

Abstract

Background

Overexpression of α-synuclein (SNCA) in families with multiplication mutations causes parkinsonism and subsequent dementia, characterized by diffuse Lewy Body disease post-mortem. Genetic variability in SNCA contributes to risk of idiopathic Parkinson's disease (PD), possibly as a result of overexpression. SNCA downregulation is therefore a valid therapeutic target for PD.

Results

We have identified human and murine-specific siRNA molecules which reduce SNCA in vitro. As a proof of concept, we demonstrate that direct infusion of chemically modified (naked), murine-specific siRNA into the hippocampus significantly reduces SNCA levels. Reduction of SNCA in the hippocampus and cortex persists for a minimum of 1 week post-infusion with recovery nearing control levels by 3 weeks post-infusion.

Conclusion

We have developed naked gene-specific siRNAs that silence expression of SNCA in vivo. This approach may prove beneficial toward our understanding of the endogenous functional equilibrium of SNCA, its role in disease, and eventually as a therapeutic strategy for α-synucleinopathies resulting from SNCA overexpression.