[HTML][HTML] In vivo silencing of alpha-synuclein using naked siRNA
J Lewis, H Melrose, D Bumcrot, A Hope, C Zehr… - Molecular …, 2008 - Springer
Molecular neurodegeneration, 2008•Springer
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 …
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 …
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.
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