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G-rich motifs within phosphorothioate-based antisense oligonucleotides (ASOs) drive activation of FXN expression through indirect effects

ABSTRACT: Evaluation of the effect of 3 ASOs targeting FXN on mRNA levels

ORGANISM(S): Homo sapiens

PROVIDER: GSE205526 | GEO | 2022/10/28

REPOSITORIES: GEO

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G-rich motifs within phosphorothioate-based antisense oligonucleotides (ASOs) drive activation of FXN expression through indirect effects.

Project description: Not available

| S-EPMC9825156 | biostudies-literature

G-rich motifs within phosphorothioate-based antisense oligonucleotides (ASOs) drive activation of FXN expression through indirect effects

Project description:G-rich motifs within phosphorothioate-based antisense oligonucleotides (ASOs) drive activation of FXN expression through indirect effects

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Molecular phenotyping of antisense oligonucleotides (ASOs) in immortalized proximal tubule epithelial cells (PTEC-TERT1)

Project description:Molecular phenotyping quantifies expression of pathway reproter genes by next-generation sequencing of pre-defined amplicons. We applied the technology to quantify pathway-level impact of ASOs to PTECs in the presence and absence of exogeneous EGF.

2017-03-13 | GSE83392 | GEO

Correction of splicing defect in compound heterozygous FRDA patient carrying FXN 165+5G>C point mutation.

Project description:Friedreich’s ataxia is an autosomal recessive disease caused by mutations in the FXN gene. Approximately 95% of patients harbor homozygous GAA repeat expansion in the intron 1 of the FXN, while the remaining 5% are compound heterozygotes carrying GA expansion on 1 allele and point mutation on the other allele. Here, we characterized a G to C transversion in position 5 of the intron 1 of the FXN. Mutation results in profound downregulation of FXN mRNA and protein levels. Transcriptome and RT-PCR analyses demonstrated aberrant splicing of the FXN gene caused by this mutation that can be at least in part corrected with antisense oligonucleotides (ASOs) targeting intron 1.

2025-07-10 | GSE262763 | GEO

mRNA-specific readthrough of nonsense codons by antisense oligonucleotides (R-ASOs).

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Knockdown of circular RNAs using LNA-modified antisense oligonucleotides

Project description:Circular RNAs (circRNAs) constitute an abundant class of covalently closed non-coding RNA molecules that are formed by backsplicing from eukaryotic protein-coding genes. Recent studies have shown that circRNAs can act as microRNA or protein decoys as well as transcriptional regulators. However, the functions of most circRNAs are still poorly understood. Because circRNA sequences overlap with their linear parent transcripts, depleting specific circRNAs without affecting host gene expression remains a challenge. Here, we assessed the utility of LNA-modified antisense oligonucleotides (ASOs) to knock down circRNAs for loss-of-function studies. We identified 5807 circRNAs in total RNA sequencing data from 4 liver cancer cell lines and used the back splice junction (BSJ) sequences of 7 validated circRNAs as target sites for designing different LNA-modified ASOs for circRNA knockdown. We found that while most RNase H-dependent gapmer ASOs mediate effective knockdown of their target circRNAs, some gapmers reduce the levels of the linear parent transcript and may also cause degradation of unintended off-targets. The circRNA targeting specificity can be enhanced using design-optimized gapmer ASOs or LNA/DNA mixmer ASOs, which display potent and specific circRNA knockdown with a minimal effect on the host genes or predicted off-targets. In summary, our results demonstrate that LNA-modified ASOs complementary to BSJ sequences mediate robust knockdown of circRNAs in vitro and, thus, represent a useful tool to explore the biological roles of circRNAs in loss-of-function studies in cultured cells and animal models.

2022-11-01 | GSE145592 | GEO

Antisense oligonucleotides targeting nuclear RNA for in vivo correction of myotonic dystrophy

Project description:This study examined the effects of antisense oligonucleotides (ASOs) on the muscle transcriptome in a transgenic mouse model of myotonic dystrophy. Two ASOs were tested in HSALR transgenic mice. Both of the ASOs targeted mRNA from a human skeletal actin (hACTA1) transgene. This transgene contains an expanded CTG repeat in the 3M-bM-^@M-^Y untranslated region (UTR) (Mankodi et al M-bM-^@M-^\Myotonic dystrophy in transgenic mice expressing an expanded CUG repeatM-bM-^@M-^] Science 2000; 289:1769-72). ASO 445235 targeted the hACTA1 transcript in the 3M-bM-^@M-^Y UTR, downstream from the expanded repeat. ASO 190401 targeted the hACTA1 transcript in the coding region. The HSALR mice received 4 weeks of biweekly subcutaneous injections of vehicle (saline), ASO 190401, or ASO 445236 (n = 4 per group), at a dose of 25 mg/kg per injection. Wild-type mice of the same strain background received saline injections (n = 4). One week after the final injection, quadriceps muscle was harvested for RNA analysis. Four conditions, four arrays per condition, to compare WT and HSALR trangenic mice without treatment (saline) and to examine the effect of two oligos (vs. saline) in the HSALR transgenic mice.

2012-06-27 | E-GEOD-38962 | biostudies-arrayexpress

Targeting Smyd3 by antisense oligonucleotides attenuates liver tumor growth

Project description:We investigated whether pharamacological inhibition of Smyd3 by antisense oligonucleotides (ASOs) can influence diethylnitrosamine (DEN)-induced liver cancer development. Our phenotypic analyses, among others, included gene expression profiling.

2020-06-24 | GSE153077 | GEO

Evaluation of off-target effects of gapmer antisense oligonucleotides using human cells

Project description:Antisense oligonucleotide (ASO) has the potential to induce off-target effects due to complementary binding between the ASO and unintended RNA with a sequence similar to the target RNA. In this study, we evaluated off-target effects of gapmer ASOs, which cleave the target RNA in an RNase H-dependent manner, by introducing the ASO into human cells and performing microarray analysis. Our data indicate that gapmer ASOs induce off-target effects depending on the degree of complementarity between the ASO and off-target candidate genes. Based on our results, we also propose a scheme for assessment of off-target effects of gapmer ASOs.

2021-12-08 | GSE190473 | GEO

Antisense oligonucleotides targeting the miR-29b binding site in the GRN mRNA increase progranulin translation

Project description:Heterozygous GRN (progranulin) mutations cause frontotemporal dementia (FTD) due to haploinsufficiency, and increasing progranulin levels is a major therapeutic goal. Several microRNAs, including miR-29b, negatively regulate progranulin protein levels. Antisense oligonucleotides (ASOs) are emerging as a promising therapeutic modality for neurological diseases, but strategies for increasing target protein levels are limited. Here, we tested the efficacy of ASOs as enhancers of progranulin expression by sterically blocking the miR-29b binding site in the 3' UTR of the human GRN mRNA. We found 16 ASOs that increase progranulin protein in a dose-dependent manner in neuroglioma cells. A subset of these ASOs also increased progranulin protein in iPSC-derived neurons and in a humanized GRN mouse model. In FRET-based assays, the ASOs effectively competed miR-29b from binding to the GRN 3' UTR RNA. The ASOs increased levels of newly synthesized progranulin protein by increasing its translation, as revealed by polysome profiling. Together, our results demonstrate that ASOs can be used to effectively increase target protein levels by partially blocking miR binding sites. This ASO strategy may be therapeutically feasible for progranulin-deficient FTD as well as other conditions of haploinsufficiency.

2022-08-01 | GSE188498 | GEO

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