TY - JOUR
T1 - In vivo silencing of alpha-synuclein using naked siRNA
AU - Lewis, Jada
AU - Melrose, Heather
AU - Bumcrot, David
AU - Hope, Andrew
AU - Zehr, Cynthia
AU - Lincoln, Sarah
AU - Braithwaite, Adam
AU - He, Zhen
AU - Ogholikhan, Sina
AU - Hinkle, Kelly
AU - Kent, Caroline
AU - Toudjarska, Ivanka
AU - Charisse, Klaus
AU - Braich, Ravi
AU - Pandey, Rajendra K.
AU - Heckman, Michael
AU - Maraganore, Demetrius M.
AU - Crook, Julia
AU - Farrer, Matthew J.
N1 - Funding Information:
This work was funded by the Michael J. Fox Foundation (to J.L., D.B., and M.J.F.) and the Mayo Foundation (to J.L. and M.J.F.). We thank Richard Crook and Zeshan Ahmed for help with the figures and Faith Conkle, Deb Maloy and the animal care staff for ensuring animal welfare.
PY - 2008
Y1 - 2008
N2 - Background: Overexpression of -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 -synucleinopathies resulting from SNCA overexpression.
AB - Background: Overexpression of -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 -synucleinopathies resulting from SNCA overexpression.
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U2 - 10.1186/1750-1326-3-19
DO - 10.1186/1750-1326-3-19
M3 - Article
C2 - 18976489
AN - SCOPUS:58149269261
SN - 1750-1326
VL - 3
JO - Molecular neurodegeneration
JF - Molecular neurodegeneration
IS - 1
M1 - 19
ER -