title: Novel oligonucleotides containing two 3'-ends complementary to target mRNA show optimal gene-silencing activity.
abstract: Oligonucleotides are being employed for gene-silencing activity by a variety of mechanisms, including antisense, ribozyme, and siRNA. In the present studies, we designed novel oligonucleotides complementary to targeted mRNAs and studied the effect of 3'-end exposure and oligonucleotide length on gene-silencing activity. We synthesized both oligoribonucleotides (RNAs) and oligodeoxynucleotides (DNAs) with phosphorothioate backbones, consisting of two identical segments complementary to the targeted mRNA attached through their 5'-ends, thereby containing two accessible 3'-ends; these compounds are referred to as gene-silencing oligonucleotides (GSOs). RNA and/or DNA GSOs targeted to MyD88, VEGF, and TLR9 mRNAs had more potent gene-silencing activity than did antisense phosphorothioate oligonucleotides (PS-oligos) in cell-based assays and in vivo. Of the different lengths of GSOs evaluated, 19-mer long RNA and DNA GSOs had the best gene-silencing activity both in vitro and in vivo. These results suggest that GSOs are novel agents for gene silencing that can be delivered systemically with broader applicability.
authors.affiliation: Idera Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, United States.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Bhagat
authors.forename: Mallikarjuna Reddy
authors.initials: MR
authors.lastname: Putta
authors.forename: Daqing
authors.initials: D
authors.lastname: Wang
authors.forename: Dong
authors.initials: D
authors.lastname: Yu
authors.forename: Tao
authors.initials: T
authors.lastname: Lan
authors.forename: Weiwen
authors.initials: W
authors.lastname: Jiang
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Sun
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Jimmy X
authors.initials: JX
authors.lastname: Tang
authors.forename: Nicola
authors.initials: N
authors.lastname: La Monica
authors.forename: Ekambar R
authors.initials: ER
authors.lastname: Kandimalla
authors.forename: Sudhir
authors.initials: S
authors.lastname: Agrawal
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D009841:Oligonucleotides / Q000737:chemistry / Q000494:pharmacology*; D012333:RNA, Messenger / Q000737:chemistry*
chemical_list: D017931:DNA Primers; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D009841:Oligonucleotides; D012333:RNA, Messenger