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Related Concept Videos

Pre-mRNA Processing: Modification of pre-mRNA Ends01:35

Pre-mRNA Processing: Modification of pre-mRNA Ends

In eukaryotic cells, transcripts made by RNA polymerase are modified and processed before exiting the nucleus. Unprocessed RNA is called precursor mRNA or pre-mRNA to distinguish it from mature mRNA.
Once about 20-40 ribonucleotides have been joined together by RNA polymerase, a group of enzymes adds a cap to the 5' end of the growing transcript. In this process, a 5' phosphate is replaced by modified guanosine that has a methyl group attached (7-methyl guanosine). This 5' cap helps the cell...
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RNA Editing

RNA editing is a post-transcriptional modification where a precursor mRNA (pre-mRNA) nucleotide sequence is changed by base insertion, deletion, or modification. The extent of RNA editing varies from a few hundred bases, in mitochondrial DNA of trypanosomes, to a just single base, in nuclear genes of mammals. Even a single base change in the pre-mRNA can convert a codon for one amino acid into the codon for another amino acid or a stop codon. This type of re-coding can significantly affect the...

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Sequence-specific and Selective Recognition of Double-stranded RNAs over Single-stranded RNAs by Chemically Modified Peptide Nucleic Acids
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Sequence-specific and Selective Recognition of Double-stranded RNAs over Single-stranded RNAs by Chemically Modified Peptide Nucleic Acids

Published on: September 21, 2017

Chemical modification study of antisense gapmers.

Robert Stanton1, Simone Sciabola, Christopher Salatto

  • 1Oligonucleotide Therapeutic Unit, Pfizer, Cambridge, MA, USA. robert.stanton@pfizer.com

Nucleic Acid Therapeutics
|August 3, 2012
PubMed
Summary
This summary is machine-generated.

Chemically modified antisense oligonucleotides show varied in vivo efficacy and toxicity. Unassisted in vitro assays better predict in vivo results than lipid-transfected assays for these modified nucleic acid therapies.

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Area of Science:

  • Oligonucleotide therapeutics
  • Chemical modifications of nucleic acids
  • Gene silencing mechanisms

Background:

  • Antisense oligonucleotides (ASOs) are a promising therapeutic modality for gene silencing.
  • Chemical modifications are crucial for enhancing ASO stability, potency, and reducing toxicity.
  • Understanding the impact of different chemical modifications on ASO performance is essential for drug development.

Purpose of the Study:

  • To investigate the in vitro and in vivo performance of various chemically modified antisense gapmers targeting the glucocorticoid receptor.
  • To correlate in vitro assay results (lipid-transfected vs. unassisted) with in vivo outcomes.
  • To assess the impact of modification patterns on mRNA knockdown and hepatotoxicity.

Main Methods:

  • Synthesis and evaluation of antisense gapmers with diverse chemical modifications (2'-OMe, 2'-F, MOE, LNA, G-Clamp).
  • In vitro assays including lipid-mediated transfection and unassisted (gymnotic) delivery.
  • In vivo studies in relevant models to assess mRNA knockdown and hepatotoxicity.
  • Analysis of structure-activity relationships based on modification type, position, and density.

Main Results:

  • In vivo results correlated well with unassisted in vitro assays, but not always with lipid-transfected assays.
  • G-Clamp modified ASOs showed poor in vivo knockdown compared to in vitro results.
  • LNA gapmer activity was sensitive to the number and placement of LNA modifications.
  • Subtle changes in chemical modification patterns led to significant variations in hepatotoxicity for identical sequences.

Conclusions:

  • Unassisted in vitro assays are valuable predictors of in vivo antisense oligonucleotide performance.
  • The choice and pattern of chemical modifications significantly influence both efficacy and safety (hepatotoxicity) of antisense gapmers.
  • Optimization of antisense oligonucleotide therapeutics requires careful consideration of sequence-specific and modification-dependent effects.