RNA Therapeutics Institute; Program in Molecular Medicine; Department of Medicine
Biochemistry, Biophysics, and Structural Biology | Cell and Developmental Biology | Genetics and Genomics | Molecular Biology | Neuroscience and Neurobiology | Therapeutics
The use of siRNA-based therapies for the treatment of neurodegenerative disease requires efficient, nontoxic distribution to the affected brain parenchyma, notably the striatum and cortex. Here, we describe the synthesis and activity of a fully chemically modified siRNA that is directly conjugated to docosahexaenoic acid (DHA), the most abundant polyunsaturated fatty acid in the mammalian brain. DHA conjugation enables enhanced siRNA retention throughout both the ipsilateral striatum and cortex following a single, intrastriatal injection (ranging from 6-60 mug). Within these tissues, DHA conjugation promotes internalization by both neurons and astrocytes. We demonstrate efficient and specific silencing of Huntingtin mRNA expression in both the ipsilateral striatum (up to 73%) and cortex (up to 51%) after 1 week. Moreover, following a bilateral intrastriatal injection (60 mug), we achieve up to 80% silencing of a secondary target, Cyclophilin B, at both the mRNA and protein level. Importantly, DHA-hsiRNAs do not induce neural cell death or measurable innate immune activation following administration of concentrations over 20 times above the efficacious dose. Thus, DHA conjugation is a novel strategy for improving siRNA activity in mouse brain, with potential to act as a new therapeutic platform for the treatment of neurodegenerative disorders.
drug delivery, neurodegenerative disease, siRNA
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Copyright © 2016 Official journal of the American Society of Gene and Cell Therapy. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
DOI of Published Version
Mol Ther Nucleic Acids. 2016 Aug 9;5(8):e344. doi: 10.1038/mtna.2016.50. Link to article on publisher's site
Molecular therapy. Nucleic acids
Nikan, Mehran; Osborn, Maire F.; Coles, Andrew H.; Godinho, Bruno M. D. C.; Hall, Lauren M.; Haraszti, Reka A.; Echeverria, Dimas; Aronin, Neil; Hassler, Matthew R.; and Khvorova, Anastasia, "Docosahexaenoic Acid Conjugation Enhances Distribution and Safety of siRNA upon Local Administration in Mouse Brain" (2016). RNA Therapeutics Institute Publications. 13.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.