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PMID: 18461053 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Novel dual inhibitory function aptamer-siRNA delivery system for HIV-1 therapy.

Molecular therapy : the journal of the American Society of Gene Therapy ·Vol. 16 ·No. 8 ·2008-08-00 ·Pages 1481-9

Zhou J, Li H, Li S, Zaia J, Rossi JJ

Abstract

The successful use of small interfering RNAs (siRNAs) for therapeutic purposes requires safe and efficient delivery to specific cells and tissues. In this study, we demonstrate cell type-specific delivery of anti-human immunodeficiency virus (anti-HIV) siRNAs through fusion to an anti-gp120 aptamer. The envelope glycoprotein is expressed on the surface of HIV-1-infected cells, allowing binding and internalization of the aptamer-siRNA chimeric molecules. We demonstrate that the anti-gp120 aptamer-siRNA chimera is specifically taken up by cells expressing HIV-1 gp120, and that the appended siRNA is processed by Dicer; this releases an anti-tat/rev siRNA which, in turn, inhibits HIV replication. We show for the first time a dual functioning aptamer-siRNA chimera in which both the aptamer and the siRNA portions have potent anti-HIV activities. We also show that gp120 expressed on the surface of HIV-infected cells can be used for aptamer-mediated delivery of anti-HIV siRNAs.

MeSH Terms
Animals Aptamers, Nucleotide/genetics Blotting, Northern CHO Cells Cricetinae Cricetulus Eukaryotic Cells/metabolism,virology Gene Silencing HCT116 Cells HIV Envelope Protein gp120/genetics HIV Infections/genetics,therapy HIV-1/genetics Humans RNA, Small Interfering/genetics Reverse Transcriptase Polymerase Chain Reaction Transcription, Genetic Transfection/methods
Chemicals
Aptamers, Nucleotide HIV Envelope Protein gp120 RNA, Small Interfering
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Zhou Jiehua
Division of Molecular Biology, Beckman Research Institute of the City of Hope, Duarte, California, USA.
Li Haitang
Li Shirley
Zaia John
Rossi John J
References (50)
50 references, click to expand
  1. In vivo activity of nuclease-resistant siRNAs.
    RNA. 2004 May;10(5):766-71 PMID: 15100431
  2. Aptamer mediated siRNA delivery.
    Nucleic Acids Res. 2006 Jun 01;34(10):e73 PMID: 16740739
  3. Electro-transfer of small interfering RNA ameliorated arthritis in rats.
    Biochem Biophys Res Commun. 2005 Oct 28;336(3):903-8 PMID: 16179161
  4. Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase.
    Science. 1990 Aug 3;249(4968):505-10 PMID: 2200121
  5. Peptide-based strategy for siRNA delivery into mammalian cells.
    Methods Mol Biol. 2005;309:251-60 PMID: 15990405
  6. In vitro selection of RNA molecules that bind specific ligands.
    Nature. 1990 Aug 30;346(6287):818-22 PMID: 1697402
  7. Insight into the mechanism of the peptide-based gene delivery system MPG: implications for delivery of siRNA into mammalian cells.
    Nucleic Acids Res. 2003 Jun 1;31(11):2717-24 PMID: 12771197
  8. Interferon induction by siRNAs and ssRNAs synthesized by phage polymerase.
    Nat Biotechnol. 2004 Mar;22(3):321-5 PMID: 14990954
  9. siRNA and isRNA: two edges of one sword.
    Mol Ther. 2006 Oct;14(4):463-70 PMID: 16877044
  10. Cell type-specific delivery of siRNAs with aptamer-siRNA chimeras.
    Nat Biotechnol. 2006 Aug;24(8):1005-15 PMID: 16823371
  11. Sequence-specific gene silencing in murine muscle induced by electroporation-mediated transfer of short interfering RNA.
    J Gene Med. 2004 Jan;6(1):105-10 PMID: 14716682
  12. RNAi-induced gene silencing by local electroporation in targeting brain region.
    J Neurophysiol. 2005 Jan;93(1):594-602 PMID: 15604463
  13. Fully 2'-modified oligonucleotide duplexes with improved in vitro potency and stability compared to unmodified small interfering RNA.
    J Med Chem. 2005 Feb 24;48(4):901-4 PMID: 15715458
  14. Conjugate for efficient delivery of short interfering RNA (siRNA) into mammalian cells.
    FEBS Lett. 2004 Jan 30;558(1-3):63-8 PMID: 14759517
  15. Transferrin-polycation conjugates as carriers for DNA uptake into cells.
    Proc Natl Acad Sci U S A. 1990 May;87(9):3410-4 PMID: 2333290
  16. An aptamer that neutralizes R5 strains of human immunodeficiency virus type 1 blocks gp120-CCR5 interaction.
    J Virol. 2005 Nov;79(21):13806-10 PMID: 16227301
  17. RNA interference in mammalian cells by chemically-modified RNA.
    Biochemistry. 2003 Jul 8;42(26):7967-75 PMID: 12834349
  18. Aptamers: an emerging class of therapeutics.
    Annu Rev Med. 2005;56:555-83 PMID: 15660527
  19. Progress towards in vivo use of siRNAs.
    Mol Ther. 2006 Apr;13(4):644-70 PMID: 16481219
  20. A SELEX primer.
    Methods Enzymol. 1996;267:275-301 PMID: 8743323
  21. Functional polarity is introduced by Dicer processing of short substrate RNAs.
    Nucleic Acids Res. 2005 Jul 26;33(13):4140-56 PMID: 16049023
  22. Aptamers--basic research, drug development, and clinical applications.
    Appl Microbiol Biotechnol. 2005 Dec;69(4):367-74 PMID: 16283295
  23. Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs.
    Nature. 2004 Nov 11;432(7014):173-8 PMID: 15538359
  24. Protamine sulfate enhances lipid-mediated gene transfer.
    Gene Ther. 1997 Sep;4(9):961-8 PMID: 9349433
  25. Sonoporation using microbubble BR14 promotes pDNA/siRNA transduction to murine heart.
    Biochem Biophys Res Commun. 2005 Oct 14;336(1):118-27 PMID: 16125678
  26. Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs.
    Nat Biotechnol. 2005 Aug;23(8):1002-7 PMID: 16041363
  27. Modification of professional antigen-presenting cells with small interfering RNA in vivo to enhance cancer vaccine potency.
    Cancer Res. 2005 Jan 1;65(1):309-16 PMID: 15665308
  28. Characterization of stable Chinese hamster ovary cells expressing wild-type, secreted, and glycosylphosphatidylinositol-anchored human immunodeficiency virus type 1 envelope glycoprotein.
    J Virol. 1993 Dec;67(12):7060-6 PMID: 8230430
  29. Activity of stabilized short interfering RNA in a mouse model of hepatitis B virus replication.
    Hepatology. 2005 Jun;41(6):1349-56 PMID: 15880588
  30. Structural variations and stabilising modifications of synthetic siRNAs in mammalian cells.
    Nucleic Acids Res. 2003 Jun 1;31(11):2705-16 PMID: 12771196
  31. Cancer siRNA therapy by tumor selective delivery with ligand-targeted sterically stabilized nanoparticle.
    Nucleic Acids Res. 2004 Nov 01;32(19):e149 PMID: 15520458
  32. Lipidic carriers of siRNA: differences in the formulation, cellular uptake, and delivery with plasmid DNA.
    Biochemistry. 2004 Oct 26;43(42):13348-56 PMID: 15491141
  33. Sequence-specific knockdown of EWS-FLI1 by targeted, nonviral delivery of small interfering RNA inhibits tumor growth in a murine model of metastatic Ewing's sarcoma.
    Cancer Res. 2005 Oct 1;65(19):8984-92 PMID: 16204072
  34. Delivery of antisense oligodeoxyribonucleotides against the human epidermal growth factor receptor into cultured KB cells with liposomes conjugated to folate via polyethylene glycol.
    Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3318-22 PMID: 7724560
  35. RNA pseudoknots that inhibit human immunodeficiency virus type 1 reverse transcriptase.
    Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):6988-92 PMID: 1379730
  36. Escort aptamers: a delivery service for diagnosis and therapy.
    J Clin Invest. 2000 Oct;106(8):923-8 PMID: 11032850
  37. Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody.
    Nature. 1998 Jun 18;393(6686):648-59 PMID: 9641677
  38. Indicator cell lines for detection of primary strains of human and simian immunodeficiency viruses.
    Virology. 1997 Jun 23;233(1):193-8 PMID: 9201229
  39. Strategies for silencing human disease using RNA interference.
    Nat Rev Genet. 2007 Mar;8(3):173-84 PMID: 17304245
  40. Cell-specific targeting of nanoparticles by multivalent attachment of small molecules.
    Nat Biotechnol. 2005 Nov;23(11):1418-23 PMID: 16244656
  41. Delivery of siRNA and siRNA expression constructs to adult mammals by hydrodynamic intravascular injection.
    Methods Enzymol. 2005;392:336-50 PMID: 15644191
  42. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans.
    Nature. 1998 Feb 19;391(6669):806-11 PMID: 9486653
  43. Structural characterization of an anti-gp120 RNA aptamer that neutralizes R5 strains of HIV-1.
    RNA. 2005 Jun;11(6):873-84 PMID: 15923374
  44. Stable expression of shRNAs in human CD34+ progenitor cells can avoid induction of interferon responses to siRNAs in vitro.
    Nat Biotechnol. 2006 May;24(5):566-71 PMID: 16648841
  45. Cyclodextrin-modified polyethylenimine polymers for gene delivery.
    Bioconjug Chem. 2004 Jul-Aug;15(4):831-40 PMID: 15264871
  46. Aptamers against extracellular targets for in vivo applications.
    Biochimie. 2005 Sep-Oct;87(9-10):921-30 PMID: 15963620
  47. Synthetic dsRNA Dicer substrates enhance RNAi potency and efficacy.
    Nat Biotechnol. 2005 Feb;23(2):222-6 PMID: 15619617
  48. Structures of HIV-1 gp120 envelope glycoproteins from laboratory-adapted and primary isolates.
    Structure. 2000 Dec 15;8(12):1329-39 PMID: 11188697
  49. Lipid-mediated siRNA delivery down-regulates exogenous gene expression in the mouse brain at picomolar levels.
    J Gene Med. 2005 Feb;7(2):198-207 PMID: 15515135
  50. Neutralization of infectivity of diverse R5 clinical isolates of human immunodeficiency virus type 1 by gp120-binding 2'F-RNA aptamers.
    J Virol. 2003 Dec;77(23):12692-8 PMID: 14610191
Article Info
Journal
Molecular therapy : the journal of the American Society of Gene Therapy
Abbr.
Mol Ther
ISSN
1525-0024
DOI
10.1038/mt.2008.92
Published
2008-08-00
Epub
2008-00-06
Pages
1481-9
Language
English
Region
United States
NLM ID
100890581
PMCID
PMC2727148
Subset
IM
Grants
NIAID NIH HHS · R01 AI042552-11 · United States
NIAID NIH HHS · R37 AI029329 · United States
NIAID NIH HHS · R37 AI029329-20 · United States
NIAID NIH HHS · R01 AI042552 · United States
NHLBI NIH HHS · R01 HL074704 · United States
NHLBI NIH HHS · R01 HL074704-05A2 · United States
Corrections
CommentIn
PMID: 18660800
External Links
PubMed source DOI: 10.1038/mt.2008.92 PMC Full Text View journal details
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