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Evoking potent RNAi response in cancer using novel 2’-OMe-phosphorodithioated modified siRNAs

ABSTRACT: Use of MePS2-modified siRNAs to target GRAM Domain Containing 1B (GRAMD1B), a novel protein in taxane resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE54459 | GEO | 2014/03/10

SECONDARY ACCESSION(S): PRJNA236554

REPOSITORIES: GEO

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Evoking potent RNAi response in cancer using novel 2’-OMe-phosphorodithioated modified siRNAs

Project description:Use of MePS2-modified siRNAs to target GRAM Domain Containing 1B (GRAMD1B), a novel protein in taxane resistance. Two groups of samples are included: 1. siControl treated HeyA8-MDR and 2. siGRAMD1B treated HeyA8-MDR. Gene expression profiles of siGRAMD1B-HeyA8-MDR cells were compared to that of siControl-HeyA8MDR cells.

2014-03-10 | E-GEOD-54459 | biostudies-arrayexpress

Identification of cell signaling pathway associated miRNAs in cancer cells using a systems biological approach: potent RNAi response in cancer using novel 2’-OMe-phosphorodithioated modified siRNAs

Project description:MicroRNAs (miRNAs) are single-stranded, non-coding RNA molecules and on average only 22 nucleotides long that regulate gene expression at the post-transcriptional level. Target predictions of miRNA based on sequence are limited due to too many candidates resulting in high false positives. We generated the Association score matrix and miRNA-pathway association map. To validate our approach, we used miR-500 as an example to investigate the hypothetical target regulation mechanisms. We confirmed in-vitro that mir-500 highly is associated with ERK signaling pathway in breast cancer cells. Furthermore, we found PPFIA1 might be one of direct targets of miR-500 to regulate activating the ERK pathway. In conclusion, we developed a model system to systematically predict potential miRNA functional targets which play critical roles in cell signaling pathways from the NCI-60 genomic and proteomic data at whole genomic scale.

2016-08-01 | GSE61752 | GEO

Identification of cell signaling pathway associated miRNAs in cancer cells using a systems biological approach: potent RNAi response in cancer using novel 2â-OMe-phosphorodithioated modified siRNAs

2016-08-01 | E-GEOD-61752 | biostudies-arrayexpress

2'-OMe-phosphorodithioate-modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity.

Project description:Improving small interfering RNA (siRNA) efficacy in target cell populations remains a challenge to its clinical implementation. Here, we report a chemical modification, consisting of phosphorodithioate (PS2) and 2'-O-Methyl (2'-OMe) MePS2 on one nucleotide that significantly enhances potency and resistance to degradation for various siRNAs. We find enhanced potency stems from an unforeseen increase in siRNA loading to the RNA-induced silencing complex, likely due to the unique interaction mediated by 2'-OMe and PS2. We demonstrate the therapeutic utility of MePS2 siRNAs in chemoresistant ovarian cancer mouse models via targeting GRAM domain containing 1B (GRAMD1B), a protein involved in chemoresistance. GRAMD1B silencing is achieved in tumours following MePS2-modified siRNA treatment, leading to a synergistic anti-tumour effect in combination with paclitaxel. Given the previously limited success in enhancing siRNA potency with chemically modified siRNAs, our findings represent an important advance in siRNA design with the potential for application in numerous cancer types.

| S-EPMC4112501 | biostudies-literature

Intracellular stability of 2'-OMe-4'-thioribonucleoside modified siRNA leads to long-term RNAi effect.

Project description:Chemically modified siRNAs are expected to have resistance toward nuclease degradation and good thermal stability in duplex formation for in vivo applications. We have recently found that 2'-OMe-4'-thioRNA, a hybrid chemical modification based on 2'-OMeRNA and 4'-thioRNA, has high hybridization affinity for complementary RNA and significant resistance toward degradation in human plasma. These results prompted us to develop chemically modified siRNAs using 2'-OMe-4'-thioribonucleosides for therapeutic application. Effective modification patterns were screened with a luciferase reporter assay. The best modification pattern of siRNA, which conferred duration of the gene-silencing effect without loss of RNAi activity, was identified. Quantification of the remaining siRNA in HeLa-luc cells using a Heat-in-Triton (HIT) qRT-PCR revealed that the intracellular stability of the siRNA modified with 2'-OMe-4'-thioribonucleosides contributed significantly to the duration of its RNAi activity.

| S-EPMC3384325 | biostudies-literature

Forward and robust selection of the most potent and noncellular toxic siRNAs from RNAi libraries.

Project description:Use of highly potent small interfering RNAs (siRNAs) can substantially reduce dose-dependent cytotoxic and off-target effects. We developed a genetic forward approach by fusing the cytosine deaminase gene with targets for the robust identification of highly potent siRNAs from RNA interference (RNAi) libraries that were directly delivered into cells via bacterial invasion. We demonstrated that two simple drug selection cycles performed conveniently in a single container predominately enriched two siRNAs targets the MVP gene (siMVP) and one siRNA targets the egfp gene (siEGFP) in surviving cells and these proved to be the most effective siRNAs reported. Furthermore, the potent siRNAs isolated from the surviving cells possessed noncellular toxic characteristics. Interestingly, the length of highly potent siMVPs identified could be as short as 16-mer, and increasing the length of their native sequences dramatically reduced RNAi potency. These results suggest that the current approach can robustly discover the most potent and nontoxic siRNAs in the surviving cells, and thus has great potential in facilitating RNAi applications by minimizing the dose-dependent and sequence nonspecific side effects of siRNAs.

| S-EPMC2615601 | biostudies-literature

eIF4A3 - Modified iCLIP

Project description:eIF4A3 - Modified iCLIP

| PRJEB11647 | ENA

PTBP1 - Modified iCLIP

Project description:PTBP1 - Modified iCLIP

| PRJEB15236 | ENA

Overcoming GNA/RNA Base-Pairing Limitations Using Isonucleotides Improves the Pharmacodynamic Activity of ESC+ GalNAc-siRNAs

Project description:We report the impact of two pairs of GNA nucleotides, the native GNA-C and -G compared with the isomeric GNA-isoC and -isoG, on the on- and off-target activity of chemically modified siRNAs in primary mouse hepatocytes by RNA sequencing. We found that both GNA-C and -isoC mitigate the suppression of off-targets in a similar fashion, however, GNA-isoG was less efficacious in the mitigation of off-targets as the native GNA-G. This study informs the further design of more potent and specific chemically modified siRNAs for potential application in RNAi therapeutics.

2021-09-24 | GSE183164 | GEO

A Simple and Cost-Effective Approach for In Vitro Production of Sliced siRNAs as Potent Triggers for RNAi.

Project description:We have studied the molecular properties of in-vitro-transcribed sliced small interfering RNAs (tsli-siRNAs) as an alternative RNAi agent for chemically synthesized siRNA. We describe here a simple and cost-effective procedure for high-purity production of tsli-siRNA using bacteriophage T7 RNA polymerases. tsli-siRNAs exhibit potent gene knockdown effects, with efficacy comparable with that of chemically synthesized sli-siRNAs and classical siRNAs. Furthermore, we found that it is very easy to prepare potent tsli-siRNAs with modified bases, such as 2'-fluorine- or biotin-16-modified tsli-siRNAs. tsli-siRNAs can cause a mild innate immune response, which can be easily eliminated by alkaline phosphatase treatment. On the other hand, this feature, which can be useful as a trigger of the innate immune response, can be enhanced by polynucleotide kinase treatment. Because of the simplicity of preparation and purification, the procedure presented here could be useful for the production of RNAi or immunostimulatory reagents.

| S-EPMC5537206 | biostudies-other

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