α-synuclein suppression by targeted small interfering rna in the primate substantia nigraα-synuclein抑制通过有针对性的小干扰rna在灵长类动物黑质.pdfVIP

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α-synuclein suppression by targeted small interfering rna in the primate substantia nigraα-synuclein抑制通过有针对性的小干扰rna在灵长类动物黑质.pdf

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α-synuclein suppression by targeted small interfering rna in the primate substantia nigraα-synuclein抑制通过有针对性的小干扰rna在灵长类动物黑质

a-Synuclein Suppression by Targeted Small Interfering RNA in the Primate Substantia Nigra 1,2 3 4 5 6 Alison L. McCormack , Sally K. Mak , Jaimie M. Henderson , David Bumcrot , Matthew J. Farrer , Donato A. Di Monte1,2* 1 German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany, 2 SRI International, Menlo Park, California, United States of America, 3 The Parkinson’s Institute, Sunnyvale, California, United States of America, 4 Stanford University, Stanford, California, United States of America, 5 Alnylam Pharmaceuticals, Cambridge, Massachusetts, United States of America, 6 Mayo Clinic College of Medicine, Jacksonville, Florida, United States of America Abstract The protein a-synuclein is involved in the pathogenesis of Parkinson’s disease and other neurodegenerative disorders. Its toxic potential appears to be enhanced by increased protein expression, providing a compelling rationale for therapeutic strategies aimed at reducing neuronal a-synuclein burden. Here, feasibility and safety of a-synuclein suppression were evaluated by treating monkeys with small interfering RNA (siRNA) directed against a-synuclein. The siRNA molecule was chemically modified to prevent degradation by exo- and endonucleases and directly infused into the left substantia nigra. Results compared levels of a-synuclein mRNA and protein in the infused (left) vs. untreated (right) hemisphere and revealed a significant 40–50% suppression of a-synuclein expression. These findings could not be attributable to non-specific effects of siRNA infusion since treatment of a separate set of animals with luciferase-targeting siRNA produced no changes in a- synuclein. Infusion with a-synuclein siRNA, while lowering a-synuclein expression, had no o