MicroRNAs (miRNAs) are an abundant class of non-coding RNAs that are believed to be important in many biological processes through regulation of gene expression. The precise molecular function of miRNAs in mammals is largely unknown and a better understanding will require loss-of-function studies in vivo. Here we show that a novel class of chemically engineered oligonucleotides, termed 'antagomirs', are efficient and specific silencers of endogenous miRNAs in mice. Intravenous administration of antagomirs against miR-16, miR-122, miR-192 and miR-194 resulted in a marked reduction of corresponding miRNA levels in liver, lung, kidney, heart, intestine, fat, skin, bone marrow, muscle, ovaries and adrenals. The silencing of endogenous miRNAs by this novel method is specific, efficient and long-lasting. The biological significance of silencing miRNAs with the use of antagomirs was studied for miR-122, an abundant liver-specific miRNA. Gene expression and bioinformatic analysis of messenger RNA from antagomir-treated animals revealed that the 3' untranslated regions of upregulated genes are strongly enriched in miR-122 recognition motifs, whereas downregulated genes are depleted in these motifs. Analysis of the functional annotation of downregulated genes specifically predicted that cholesterol biosynthesis genes would be affected by miR-122, and plasma cholesterol measurements showed reduced levels in antagomir-122-treated mice. Our findings show that antagomirs are powerful tools to silence specific miRNAs in vivo and may represent a therapeutic strategy for silencing miRNAs in disease.

https://www.gene-quantification.de/kruetzfeld-antagomirs-2005.pdf

Silencing of microRNAs in vivo with ‘antagomirs’

https://cdr.lib.unc.edu/downloads/3f4627532

The Somatic Genomic Landscape of Glioblastoma

In recent years, the olefin metathesis reaction has attracted widespread attention as a versatile carbon−carbon bond-forming method. Many new applications have become possible because of major advances in catalyst design. State-of-the-art ruthenium catalysts are not only highly active but also compatible with most functional groups and easy to use. This Account traces the ideas and discoveries that were instrumental in the development of these catalysts, with particular emphasis on (PCy3)2Cl2RuCHPh and its derivatives. The discussion includes an analysis of trends in catalyst activity, a description of catalysts coordinated with N-heterocyclic carbene ligands, and an overview of ongoing work to improve the activity, stability, and selectivity of this family of L2X2RuCHR complexes.

http://web4.uwindsor.ca/users/j/jlichaa/reference.nsf/0/10ff8b04ff3a317885256d88005720f6/$FILE/acr-2001-34-18-metath-grubbs.pdf

The Development of L2X2RuCHR Olefin Metathesis Catalysts: An Organometallic Success Story

In the 10 years that have passed since the Nobel prize-winning discovery of RNA interference (RNAi), billions of dollars have been invested in the therapeutic application of gene silencing in humans. Today, there are promising data from ongoing clinical trials for the treatment of age-related macular degeneration and respiratory syncytial virus. Despite these early successes, however, the widespread use of RNAi therapeutics for disease prevention and treatment requires the development of clinically suitable, safe and effective drug delivery vehicles. Here, we provide an update on the progress of RNAi therapeutics and highlight novel synthetic materials for the encapsulation and intracellular delivery of nucleic acids.

Knocking down barriers: advances in siRNA delivery

We describe the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer.

The somatic genomic landscape of glioblastoma

Ni(II)-Catalyzed Reactions of Free D-Fructose Derivatives Modified at Positions C-5 and/or C-6.

La presente invention concerne un acide oligoribonucleique double brin modifie (ARNdb) possedant une stabilite accrue dans des cellules et des liquides biologiques, ainsi que des methodes destinees a la fabrication et a l'identification d'ARNdb possedant une stabilite accrue et a l'utilisation d'ARNdb pour inhiber l'expression ou la fonction d'un gene cible.

Acide ribonucleique double brin resistant aux nucleases

The present invention relates to systems and compositions for targeted delivery of RNA interference (RNAi) nucleotides to hepatocytes in vivo. Targeted RNAi polynucleotides are administered together with co-targeted delivery polymers. The polymers provide membrane penetration function for movement of the RNAi nucleotides from outside the cell to inside the cell. Reversible modification provides physiological responsiveness to the delivery polymers.

CONJUGATE DELIVERY SYSTEM AND COMPOSITION FOR TARGETED DELIVERY OF SMALL INTERFERING RNA (siRNA) AND PROCESS FOR PREPARING THE COMPOSITION

Doppelsträngige ribonukleinsäure mit verbesserter wirksamkeit in einem organismus

La presente invention concerne des compositions pour l'administration ciblee de polynucleotides d'interference ARN (ARNi) a une cellule in vivo. Le modulateur pharmacocinetique ameliore le ciblage in vivo en comparaison au ligand de ciblage seul. Des polynucleotides ARNi cibles par une fraction de ciblage ligand de ciblage-modulateur pharmacocinetique peuvent etre administres in vivo seuls ou conjointement a des polymeres d'administration co-cibles.

Philipp Hadwiger

Papers

Ni(II)-Catalyzed Reactions of Free D-Fructose Derivatives Modified at Positions C-5 and/or C-6.

Acide ribonucleique double brin resistant aux nucleases

CONJUGATE DELIVERY SYSTEM AND COMPOSITION FOR TARGETED DELIVERY OF SMALL INTERFERING RNA (siRNA) AND PROCESS FOR PREPARING THE COMPOSITION

Doppelsträngige ribonukleinsäure mit verbesserter wirksamkeit in einem organismus

Fraction de ciblage complexe de galactose-modulateur pharmacocinétique pour arnsi