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07:24
Identification of RNAs Engaged in Direct RNA-RNA Interaction with a Long Non-Coding RNA
Published on: July 9, 2021
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Development of a Method for Profiling Protein Interactions with LNA-Modified Antisense Oligonucleotides Using Protein
Satoko Kakiuchi-Kiyota1, Lawrence O Whiteley2, Anne M Ryan1
11 Drug Safety Research and Development, Pfizer, Inc. , Groton, Connecticut.
Nucleic Acid Therapeutics
|December 9, 2015
Summary
Toxic locked nucleic acid (LNA) gapmers bind more hepatocellular proteins, contributing to liver toxicity. This increased protein binding, alongside sequence-dependent gene modulation, causes LNA gapmer-induced hepatotoxicity.
Area of Science:
- Pharmacology
- Molecular Biology
- Hepatology
Background:
- Locked nucleic acid (LNA) gapmers are effective antisense oligonucleotides for inhibiting target RNA expression.
- Nontarget-mediated hepatotoxicity limits the development of LNA gapmers.
- Increased binding of hepatocellular proteins to toxic LNA gapmers is a potential mechanism for this toxicity.
Purpose of the Study:
- To investigate the protein binding propensity of LNA gapmers with varying toxicity.
- To understand the relationship between protein binding, gene modulation, and LNA gapmer-induced hepatotoxicity.
Main Methods:
- Human protein microarrays were used to assess protein binding to nontoxic (NTS-1), toxic (TS-2), and highly toxic (HTS-3) LNA gapmers.
- Previous transcription profiling of mouse liver RNA was utilized for comparison.
Main Results:
- Toxic LNA gapmers (TS-2 and HTS-3) bound a greater number of proteins, including those linked to hepatotoxicity and hepatic system disorders, compared to the nontoxic NTS-1.
- The protein binding profiles of TS-2 and HTS-3 were similar and did not differentiate proteins contributing to severe toxicity.
- Previous studies showed TS-2 and HTS-3 modulated different transcriptional pathways, leading to hepatotoxicity.
Conclusions:
- Both sequence-dependent transcription modulation and increased protein binding of toxic LNA gapmers contribute to hepatotoxicity.
- Understanding these mechanisms can guide the development of safer LNA gapmer therapeutics.
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