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RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform.
  • C. Bennett, E. Swayze
  • Biology, Medicine
  • Annual review of pharmacology and toxicology
  • 6 January 2010
The molecular mechanisms by which antisense oligonucleotides can be designed to modulate RNA function in mammalian cells and how synthetic oligon nucleotides behave in the body are focused on. Expand
Targeted delivery of antisense oligonucleotides to hepatocytes using triantennary N-acetyl galactosamine improves potency 10-fold in mice
Triantennary N-acetyl galactosamine (GalNAc, GN3), a high-affinity ligand for the hepatocyte-specific asialoglycoprotein receptor (ASGPR), enhances the potency of second-generation gapmer antisenseExpand
SAR by MS: discovery of a new class of RNA-binding small molecules for the hepatitis C virus: internal ribosome entry site IIA subdomain.
A new class of small molecules that bind the HCV RNA IRES IIA subdomain with sub-micromolar affinity is reported and activity in a cellular replicon assay at concentrations comparable to their KD for the RNA target is demonstrated. Expand
Fully 2'-modified oligonucleotide duplexes with improved in vitro potency and stability compared to unmodified small interfering RNA.
This is the first report of such a potent fully modified siRNA motif, consisting entirely of 2'-O-methyl and 2'-fluoro nucleotides, which may represent a useful design for therapeutic oligonucleotides. Expand
Positional effect of chemical modifications on short interference RNA activity in mammalian cells.
The study of the antisense strand of siRNAs demonstrated that activity depends on the position of the modifications in the sequence, and guidelines to design effective and stable si RNAs for RNA interference mediated therapeutic applications are provided. Expand
Short antisense oligonucleotides with novel 2'-4' conformationaly restricted nucleoside analogues show improved potency without increased toxicity in animals.
The potency of second generation antisense oligonucleotides in animals was increased 3- to 5 -fold (ED(50) approximately 2-5 mg/kg) without producing hepatotoxicity, by employing novel nucleoside modifications that combine structural elements of 2'-O-methoxyethyl residues and locked nucleic acid. Expand
Single-Stranded siRNAs Activate RNAi in Animals
Single-stranded siRNAs (ss-siRNAs) that silence gene expression in animals absent lipid formulation are described and it is found that the passenger strand is not necessary for potent gene silencing. Expand
Single-Stranded RNAs Use RNAi to Potently and Allele-Selectively Inhibit Mutant Huntingtin Expression
RNAi by single-stranded siRNAs is described, demonstrating that chemically modified ss-siRNAs function through the RNAi pathway and provide allele-selective compounds for clinical development. Expand
Potent inhibition of microRNA in vivo without degradation
This work has identified a novel 2′-fluoro/2′-methoxyethyl modified ASO motif with dramatically improved in vivo potency which does not cause a decrease in mature miRNA levels and shows there are multiple mechanisms of miRNA inhibition by ASOs. Expand
Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy
Data from a mouse model of tauopathy and antisense oligonucleotides that reduce tau prevent neuronal loss and reverse tau deposition and seeding and support investigation of a tau-lowering therapy in human patients who have t Tau-positive inclusions even after pathological t Tau deposition has begun. Expand