Pharmacokinetics, biodistribution and cell uptake of antisense oligonucleotides.

MicroRNAs (miRNAs) are a class of 20–24 nt noncoding RNAs that regulate target mRNAs post-transcriptionally by binding with imperfect complementarity in the 3′-untranslated region (3′-UTR) and inhibiting translation or RNA stability. Current understanding of miRNA biology is limited, and antisense oligonucleotide (ASO) inhibition is a powerful technique for miRNA functionalization in vitro and in vivo, and for therapeutic targeting of miRNAs. Identification of optimal ASO chemistries for targeting miRNAs is therefore of great interest. We evaluated a number of 2′-sugar and backbone ASO modifications for their ability to inhibit miR-21 activity on a luciferase reporter mRNA. ASO modifications that improved target affinity improved miRNA ASO activity, yet the positioning of high-affinity modifications also had dramatically different effects on miRNA activity, suggesting that more than affinity determined the effectiveness of the miRNA ASOs. We present data in which the activity of a modified miRNA ASO was inversely correlated to its tolerability as an siRNA passenger strand, suggesting that a similar mechanism could be involved in the dissociation of miRNA ASOs and siRNA passenger strands. These studies begin to define the factors important for designing improved miRNA ASOs, enabling more effective miRNA functionalization and therapeutic targeting.

/pdf/improved-targeting-of-mirna-with-antisense-oligonucleotides-182azdndtx.pdf

Improved targeting of miRNA with antisense oligonucleotides.

Oligomeric compounds including oligoribonucleotides and oligoribonucleosides are provided that have subsequences of 2′-pentoribofuranosyl nucleosides that activate dsRNase. The oligoribonucleotides and oligoribonucleosides can include substituent groups for increasing binding affinity to complementary nucleic acid strand as well as substituent groups for increasing nuclease resistance. The oligomeric compounds are useful for diagnostics and other research purposes, for modulating the expression of a protein in organisms, and for the diagnosis, detection and treatment of other conditions susceptible to oligonucleotide therapeutics. Also included in the invention are mammalian ribonucleases, i.e., enzymes that degrade RNA, and substrates for such ribonucleases. Such a ribonuclease is referred to herein as a dsRNase, wherein “ds” indicates the RNase's specificity for certain double-stranded RNA substrates. The artificial substrates for the dsRNases described herein are useful in preparing affinity matrices for purifying mammalian ribonuclease as well as non-degradative RNA-binding proteins.

Oligoribonucleotides and ribonucleases for cleaving RNA

2'-carbohydrate modifications in antisense oligonucleotide therapy: importance of conformation, configuration and conjugation.

Abstract Eighteen nucleic acid therapeutics have been approved for treatment of various diseases in the last 25 years. Their modes of action include antisense oligonucleotides (ASOs), splice-switching oligonucleotides (SSOs), RNA interference (RNAi) and an RNA aptamer against a protein. Among the diseases targeted by this new class of drugs are homozygous familial hypercholesterolemia, spinal muscular atrophy, Duchenne muscular dystrophy, hereditary transthyretin-mediated amyloidosis, familial chylomicronemia syndrome, acute hepatic porphyria, and primary hyperoxaluria. Chemical modification of DNA and RNA was central to making drugs out of oligonucleotides. Oligonucleotide therapeutics brought to market thus far contain just a handful of first- and second-generation modifications, among them 2′-fluoro-RNA, 2′-O-methyl RNA and the phosphorothioates that were introduced over 50 years ago. Two other privileged chemistries are 2′-O-(2-methoxyethyl)-RNA (MOE) and the phosphorodiamidate morpholinos (PMO). Given their importance in imparting oligonucleotides with high target affinity, metabolic stability and favorable pharmacokinetic and -dynamic properties, this article provides a review of these chemistries and their use in nucleic acid therapeutics. Breakthroughs in lipid formulation and GalNAc conjugation of modified oligonucleotides have paved the way to efficient delivery and robust, long-lasting silencing of genes. This review provides an account of the state-of-the-art of targeted oligo delivery to hepatocytes.

/pdf/chemistry-structure-and-function-of-approved-oligonucleotide-20tev6zs.pdf

Chemistry, structure and function of approved oligonucleotide therapeutics

Second Generation of Antisense Oligonucleotides: From Nuclease Resistance to Biological Efficacy in Animals.

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Second Generation of Antisense Oligonucleotides: From Nuclease Resistance to Biological Efficacy in Animals.