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Alterman JF, Hall LM, Coles AH, et al. Hydrophobically Modified siRNAs Silence Huntingtin mRNA in Primary Neurons and Mouse Brain. Mol Ther Nucleic Acids. 2015;4:e266doi: 10.1038/mtna.2015.38.
Alterman, J. F., Hall, L. M., Coles, A. H., Hassler, M. R., Didiot, M. C., Chase, K., Abraham, J., Sottosanti, E., Johnson, E., Sapp, E., Osborn, M. F., Difiglia, M., Aronin, N., & Khvorova, A. (2015). Hydrophobically Modified siRNAs Silence Huntingtin mRNA in Primary Neurons and Mouse Brain. Molecular therapy. Nucleic acids, 4e266. https://doi.org/10.1038/mtna.2015.38
Alterman, Julia F, et al. "Hydrophobically Modified siRNAs Silence Huntingtin mRNA in Primary Neurons and Mouse Brain." Molecular therapy. Nucleic acids vol. 4 (2015): e266. doi: https://doi.org/10.1038/mtna.2015.38
Alterman JF, Hall LM, Coles AH, Hassler MR, Didiot MC, Chase K, Abraham J, Sottosanti E, Johnson E, Sapp E, Osborn MF, Difiglia M, Aronin N, Khvorova A. Hydrophobically Modified siRNAs Silence Huntingtin mRNA in Primary Neurons and Mouse Brain. Mol Ther Nucleic Acids. 2015 Dec 01;4:e266. doi: 10.1038/mtna.2015.38. PMID: 26623938; PMCID: PMC5014532.
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Mol Ther Nucleic Acids. 2015 Dec 01;4:e266. doi: 10.1038/mtna.2015.38.

Hydrophobically Modified siRNAs Silence Huntingtin mRNA in Primary Neurons and Mouse Brain.

Molecular therapy. Nucleic acids

Julia F Alterman, Lauren M Hall, Andrew H Coles, Matthew R Hassler, Marie-Cecile Didiot, Kathryn Chase, Jasmin Abraham, Emily Sottosanti, Emily Johnson, Ellen Sapp, Maire F Osborn, Marian Difiglia, Neil Aronin, Anastasia Khvorova

Affiliations

  1. RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
  2. Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
  3. Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
  4. Department of Neurology, Mass General Institute for Neurodegenerative Disease, Charlestown, Massachusetts, USA.

PMID: 26623938 PMCID: PMC5014532 DOI: 10.1038/mtna.2015.38

Abstract

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.

References

  1. Adv Drug Deliv Rev. 2015 Jun 29;87:46-51 - PubMed
  2. Oncogene. 2003 Aug 28;22(36):5712-5 - PubMed
  3. J Virol. 2003 Jul;77(13):7174-81 - PubMed
  4. Nature. 2004 Nov 11;432(7014):173-8 - PubMed
  5. J Ocul Pharmacol Ther. 2013 Dec;29(10):855-64 - PubMed
  6. Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17204-9 - PubMed
  7. J Neuropathol Exp Neurol. 2011 Jul;70(7):551-67 - PubMed
  8. J Control Release. 2012 Oct 28;163(2):125-9 - PubMed
  9. Nucleic Acids Res. 2006 Jan 12;34(1):322-33 - PubMed
  10. Nature. 1998 Feb 19;391(6669):806-11 - PubMed
  11. Nat Rev Genet. 2011 May;12(5):329-40 - PubMed
  12. J Neuroimmune Pharmacol. 2006 Jun;1(2):127-37 - PubMed
  13. J Colloid Interface Sci. 2015 Jun 1;447:8-15 - PubMed
  14. J Neurochem. 2008 Nov;107(4):1158-67 - PubMed
  15. Neuron. 1993 Nov;11(5):985-93 - PubMed
  16. Sci Rep. 2015 Jul 15;5:12166 - PubMed
  17. RNA. 2007 Apr;13(4):431-56 - PubMed
  18. Histol Histopathol. 2007 Feb;22(2):129-35 - PubMed
  19. CNS Neurol Disord Drug Targets. 2013 May 1;12(3):338-49 - PubMed
  20. Gene Ther. 1999 Jun;6(6):994-1005 - PubMed
  21. Mol Neurobiol. 2010 Jun;41(2-3):242-7 - PubMed
  22. Mol Ther. 2014 Sep;22(9):1635-42 - PubMed
  23. Cell Mol Neurobiol. 2005 Dec;25(8):1195-207 - PubMed
  24. Neuron. 2012 Jun 21;74(6):1031-44 - PubMed
  25. Mol Ther. 2006 Mar;13(3):494-505 - PubMed
  26. Nature. 2009 Jan 22;457(7228):426-33 - PubMed
  27. Nat Biotechnol. 2004 Mar;22(3):326-30 - PubMed
  28. J Neurosci Res. 2003 Aug 1;73(3):400-9 - PubMed
  29. Neuron. 1995 May;14 (5):1075-81 - PubMed
  30. Colloids Surf B Biointerfaces. 2009 Feb 1;68(2):136-44 - PubMed
  31. J Pathol. 2012 Jan;226(2):365-79 - PubMed
  32. Nat Struct Biol. 2001 Sep;8(9):746-50 - PubMed
  33. Nat Biotechnol. 2011 Apr;29(4):341-5 - PubMed
  34. Neuroreport. 1998 Mar 30;9(5):793-8 - PubMed
  35. N Am J Med Sci. 2010 Dec;2(12):598-601 - PubMed
  36. Chem Biol. 2012 Aug 24;19(8):937-54 - PubMed
  37. Nat Biotechnol. 2005 Nov;23(11):1399-405 - PubMed
  38. Biochem Biophys Res Commun. 1996 Jul 25;224(3):855-62 - PubMed
  39. Cell. 2003 Oct 17;115(2):199-208 - PubMed
  40. Mol Ther. 2014 Dec;22(12 ):2093-106 - PubMed
  41. Nat Protoc. 2007;2(9):2068-78 - PubMed
  42. Cell. 2003 Oct 17;115(2):209-16 - PubMed
  43. Development. 1992 Sep;116(1):201-11 - PubMed
  44. J Clin Invest. 2011 Feb;121(2):500-7 - PubMed
  45. J Neurosci. 2010 May 5;30(18):6171-7 - PubMed
  46. Methods Mol Biol. 2008;442:45-63 - PubMed
  47. J Neurosci. 1984 Jan;4(1):111-24 - PubMed
  48. Proc Natl Acad Sci U S A. 2004 Dec 7;101(49):17270-5 - PubMed
  49. Mol Ther. 2011 Dec;19(12 ):2178-85 - PubMed
  50. Nature. 2007 Jul 5;448(7149):39-43 - PubMed
  51. Drug Discov Today. 2008 Oct;13(19-20):842-55 - PubMed
  52. Pharmaceuticals (Basel). 2013;6(5):659-80 - PubMed
  53. Exp Neurol. 2012 Jan;233(1):463-71 - PubMed
  54. Mol Ther. 2009 Jun;17 (6):1053-63 - PubMed
  55. J Pharm Pharmacol. 2002 May;54(5):593-601 - PubMed
  56. RNA. 2012 Mar;18(3):557-68 - PubMed

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