title: Generation of a conditionally replicating adenovirus based on targeted destruction of E1A mRNA by a cell type-specific MicroRNA.
abstract: MicroRNAs have emerged as important players in tissue-specific mammalian gene regulation and have also been exploited in experimental targeting of gene expression. We have constructed a recombinant adenovirus that contains sequences complementary to the liver-specific microRNA 122 (miR122) in the 3' untranslated region of the E1A gene. In Huh7 cells, which resemble normal hepatocytes in expressing high levels of miR122, this feature resulted in strongly reduced levels of E1A mRNA and protein. This property allowed us to generate a novel recombinant adenovirus that was severely attenuated in cells of hepatic origin but replicated normally in other cells. This strategy may be useful in circumventing liver toxicity associated with the systemic delivery of oncolytic adenoviruses. These data provide the first example of exploiting differential microRNA expression patterns to alter the natural tropism of a DNA virus. In addition, these results suggest that other microRNAs expressed in a tissue- or transformation-specific manner may also be used for the targeting of adenoviral replication and that the same principle may be applied to other viruses that have shown promise as oncolytic or gene delivery platforms.
authors.affiliation: Department of Virology, Haartman Institute, University of Helsinki, Haartmaninkatu 3 (POB 21), FIN-00014 Helsinki, Finland.
authors.forename: Erkko
authors.initials: E
authors.lastname: Ylösmäki
authors.forename: Tanja
authors.initials: T
authors.lastname: Hakkarainen
authors.forename: Akseli
authors.initials: A
authors.lastname: Hemminki
authors.forename: Tapio
authors.initials: T
authors.lastname: Visakorpi
authors.forename: Raul
authors.initials: R
authors.lastname: Andino
authors.forename: Kalle
authors.initials: K
authors.lastname: Saksela
mesh_terms: D020413:3' Untranslated Regions; D000256:Adenoviridae / Q000235:genetics* / Q000254:growth & development*; D017500:Adenovirus E1A Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D002460:Cell Line; D005191:Family Characteristics; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors* / Q000235:genetics; D012367:RNA, Viral / Q000037:antagonists & inhibitors* / Q000235:genetics; D014779:Virus Replication
chemical_list: D020413:3' Untranslated Regions; D017500:Adenovirus E1A Proteins; D035683:MicroRNAs; D012333:RNA, Messenger; D012367:RNA, Viral
references.citation: Trends Genet. 2006 Mar;22(3):165-73
references.pmid: 16446010
references.citation: DNA Cell Biol. 2007 May;26(5):283-92
references.pmid: 17504024
references.citation: Oncogene. 2000 Jan 6;19(1):2-12
references.pmid: 10644974
references.citation: Gene Ther. 2001 Nov;8(21):1618-26
references.pmid: 11895000
references.citation: Virology. 1990 Dec;179(2):667-78
references.pmid: 2146801
references.citation: Cancer Res. 1997 Jul 1;57(13):2559-63
references.pmid: 9205053
references.citation: Cancer Cell. 2004 Dec;6(6):611-23
references.pmid: 15607965
references.citation: Hum Mol Genet. 2007 Apr 15;16 Spec No 1:R106-13
references.pmid: 17613543
references.citation: Mol Cell. 2004 Dec 22;16(6):861-5
references.pmid: 15610730
references.citation: Cell. 2004 Jan 23;116(2):281-97
references.pmid: 14744438
references.citation: Mol Ther. 2006 Aug;14(2):164-74
references.pmid: 16580264
references.citation: PLoS Biol. 2004 Nov;2(11):e363
references.pmid: 15502875
references.citation: Hum Gene Ther. 2002 Jan 1;13(1):143-54
references.pmid: 11779418
references.citation: Cancer Lett. 2007 Sep 8;254(2):178-216
references.pmid: 17383089
references.citation: Curr Biol. 2002 Apr 30;12(9):735-9
references.pmid: 12007417
references.citation: Oncogene. 2005 Nov 21;24(52):7802-16
references.pmid: 16299539
references.citation: J Clin Oncol. 2003 Apr 15;21(8):1498-504
references.pmid: 12697873
references.citation: J Virol. 2005 Jan;79(2):1027-35
references.pmid: 15613331
references.citation: Mol Genet Metab. 2003 Sep-Oct;80(1-2):148-58
references.pmid: 14567964
references.citation: DNA Cell Biol. 2007 May;26(5):293-300
references.pmid: 17504025
references.citation: Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2257-61
references.pmid: 16461460
references.citation: Nat Rev Cancer. 2006 Apr;6(4):259-69
references.pmid: 16557279
references.citation: Hum Gene Ther. 2004 Jan;15(1):35-46
references.pmid: 14965376
references.citation: Curr Biol. 2007 Sep 18;17(18):R789-93
references.pmid: 17878043
references.citation: Cancer Gene Ther. 2004 Oct;11(10):643-64
references.pmid: 15286681
references.citation: RNA Biol. 2004 Jul;1(2):106-13
references.pmid: 17179747
references.citation: Int J Cancer. 2004 Jul 1;110(4):475-80
references.pmid: 15122578
references.citation: Clin Cancer Res. 2002 Jan;8(1):275-80
references.pmid: 11801569
references.citation: Cell. 1986 Jan 31;44(2):283-92
references.pmid: 3943125
references.citation: Nucleic Acids Res. 2006 Jan 1;34(Database issue):D135-9
references.pmid: 16381831
references.citation: Science. 1996 Oct 18;274(5286):373-6
references.pmid: 8832876
references.citation: Mol Aspects Med. 2007 Feb;28(1):42-58
references.pmid: 17300834
references.citation: Cell. 2003 Jun 13;113(6):673-6
references.pmid: 12809598
references.citation: Methods Mol Biol. 2006;342:101-13
references.pmid: 16957370
references.citation: Nat Med. 2000 Oct;6(10):1134-9
references.pmid: 11017145
references.citation: Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2746-51
references.pmid: 16477010
references.citation: Breast Cancer Res Treat. 2008 Mar;108(1):43-55
references.pmid: 17508279
references.citation: Nat Biotechnol. 2007 Dec;25(12):1457-67
references.pmid: 18026085
references.citation: Nature. 2005 Jun 9;435(7043):834-8
references.pmid: 15944708
references.citation: Expert Opin Biol Ther. 2004 May;4(5):683-96
references.pmid: 15155160
references.citation: Mol Ther. 2008 Aug;16(8):1437-43
references.pmid: 18560417
references.citation: Nat Biotechnol. 2003 Jul;21(7):771-7
references.pmid: 12794639
references.citation: Nat Genet. 2004 Oct;36(10):1079-83
references.pmid: 15361871
references.citation: Nat Rev Cancer. 2006 Nov;6(11):857-66
references.pmid: 17060945
references.citation: Oncogene. 2005 Nov 21;24(52):7775-91
references.pmid: 16299537
references.citation: Proc Natl Acad Sci U S A. 2004 Jun 29;101(26):9740-4
references.pmid: 15210942