title: Functional in vivo delivery of multiplexed anti-HIV-1 siRNAs via a chemically synthesized aptamer with a sticky bridge.
abstract: One of the most formidable impediments to clinical translation of RNA interference (RNAi) is safe and effective delivery of the siRNAs to the desired target tissue at therapeutic doses. We previously described in vivo cell type-specific delivery of anti-HIV small-interfering RNAs (siRNAs) through covalent conjugation to an anti-gp120 aptamer. In order to improve the utility of aptamers as siRNA delivery vehicles, we chemically synthesized the gp120 aptamer with a 3' 7-carbon linker (7C3), which in turn is attached to a 16-nucleotide 2' OMe/2' Fl GC-rich bridge sequence. This bridge facilitates the noncovalent binding and interchange of various siRNAs with the same aptamer. We show here that this aptamer-bridge-construct complexed with three different Dicer substrate siRNAs (DsiRNAs) results in effective delivery of the cocktail of DsiRNAs in vivo, resulting in knockdown of target mRNAs and potent inhibition of HIV-1 replication. Following cessation of the aptamer-siRNA cocktail treatment, HIV levels rebounded facilitating a follow-up treatment with the aptamer cocktail of DsiRNAs. This follow-up injection resulted in complete suppression of HIV-1 viral loads that extended several weeks beyond the final injection. Collectively, these data demonstrate a facile, targeted approach for combinatorial delivery of antiviral and host DsiRNAs for HIV-1 therapy in vivo.
authors.affiliation: Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, Duarte, California 91010, USA.
authors.forename: Jiehua
authors.initials: J
authors.lastname: Zhou
authors.forename: C Preston
authors.initials: CP
authors.lastname: Neff
authors.forename: Piotr
authors.initials: P
authors.lastname: Swiderski
authors.forename: Haitang
authors.initials: H
authors.lastname: Li
authors.forename: David D
authors.initials: DD
authors.lastname: Smith
authors.forename: Tawfik
authors.initials: T
authors.lastname: Aboellail
authors.forename: Leila
authors.initials: L
authors.lastname: Remling-Mulder
authors.forename: Ramesh
authors.initials: R
authors.lastname: Akkina
authors.forename: John J
authors.initials: JJ
authors.lastname: Rossi
mesh_terms: D000818:Animals; D052157:Aptamers, Nucleotide / Q000235:genetics*; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000235:genetics; D015497:HIV-1 / Q000235:genetics*; D008212:Lymphocyte Depletion; D051379:Mice; D018345:Mice, Knockout; D034741:RNA, Small Interfering / Q000235:genetics*
chemical_list: D052157:Aptamers, Nucleotide; D015699:HIV Envelope Protein gp120; D034741:RNA, Small Interfering