RNA Therapeutics Institute Publications

UMMS Affiliation

RNA Therapeutics Institute; Program in Molecular Medicine; Department of Medicine

Publication Date


Document Type



Biochemistry, Biophysics, and Structural Biology | Cell and Developmental Biology | Genetics and Genomics | Molecular Biology | Neuroscience and Neurobiology | Therapeutics


Applications of RNA interference for neuroscience research have been limited by a lack of simple and efficient methods to deliver oligonucleotides to primary neurons in culture and to the brain. Here, we show that primary neurons rapidly internalize hydrophobically modified siRNAs (hsiRNAs) added directly to the culture medium without lipid formulation. We identify functional hsiRNAs targeting the mRNA of huntingtin, the mutation of which is responsible for Huntington's disease, and show that direct uptake in neurons induces potent and specific silencing in vitro. Moreover, a single injection of unformulated hsiRNA into mouse brain silences Htt mRNA with minimal neuronal toxicity. Thus, hsiRNAs embody a class of therapeutic oligonucleotides that enable simple and straightforward functional studies of genes involved in neuronal biology and neurodegenerative disorders in a native biological context.


delivery, Huntington's disease, neurodegenerative disease, RNA interference, small interfering RNA

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Copyright © 2015 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. 2015 Dec 1;4:e266. doi: 10.1038/mtna.2015.38. Link to article on publisher's site

Journal/Book/Conference Title

Molecular therapy. Nucleic acids

Related Resources

Link to Article in PubMed

PubMed ID


Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.