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Therapeutic promise of engineered nonsense suppressor tRNAs.

Authors
  • Porter, Joseph J1
  • Heil, Christina S1
  • Lueck, John D1, 2
  • 1 Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York, USA.
  • 2 Department of Neurology, University of Rochester Medical Center, Rochester, New York, USA.
Type
Published Article
Journal
Wiley Interdisciplinary Reviews - RNA
Publisher
Wiley (John Wiley & Sons)
Publication Date
Jul 01, 2021
Volume
12
Issue
4
Identifiers
DOI: 10.1002/wrna.1641
PMID: 33567469
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Nonsense mutations change an amino acid codon to a premature termination codon (PTC) generally through a single-nucleotide substitution. The generation of a PTC results in a defective truncated protein and often in severe forms of disease. Because of the exceedingly high prevalence of nonsense-associated diseases and a unifying mechanism, there has been a concerted effort to identify PTC therapeutics. Most clinical trials for PTC therapeutics have been conducted with small molecules that promote PTC read through and incorporation of a near-cognate amino acid. However, there is a need for PTC suppression agents that recode PTCs with the correct amino acid while being applicable to PTC mutations in many different genomic landscapes. With these characteristics, a single therapeutic will be able to treat several disease-causing PTCs. In this review, we will focus on the use of nonsense suppression technologies, in particular, suppressor tRNAs (sup-tRNAs), as possible therapeutics for correcting PTCs. Sup-tRNAs have many attractive qualities as possible therapeutic agents although there are knowledge gaps on their function in mammalian cells and technical hurdles that need to be overcome before their promise is realized. This article is categorized under: RNA Processing > tRNA Processing Translation > Translation Regulation. © 2021 The Authors. WIREs RNA published by Wiley Periodicals LLC.

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