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Therapeutic suppression of premature termination codons: mechanisms and clinical considerations (review)

John Karijolich1, Yi-Tao Yu2

  • 1Department of Plant and Microbial Biology, University of California, Berkeley, CA 94720, USA.

International Journal of Molecular Medicine
|June 19, 2014
PubMed

Insights

Genetic disorders caused by premature termination codons (PTCs) can be treated by promoting nonsense suppression. Small molecules and RNA-guided modifications show promise in read-through therapies for these genetic diseases.

Area of Science:

  • Molecular Biology
  • Genetics
  • Biochemistry

Background:

  • Mutations creating premature termination codons (PTCs) account for a significant portion of genetic disorders.
  • These disorders exhibit diverse phenotypes, affecting individuals across all age groups.
  • Current therapeutic strategies aim to restore protein function by overcoming PTCs.

Purpose of the Study:

  • To review current knowledge of eukaryotic translation termination.
  • To discuss methods for promoting read-through of disease-causing PTCs.
  • To identify obstacles hindering the clinical application of nonsense suppression therapies.

Main Methods:

  • Review of existing literature on translation termination and nonsense suppression.
  • Analysis of small molecules (e.g., PTC124, aminoglycosides) that modulate translation termination.
  • Examination of RNA-guided pseudouridylation as a novel nonsense suppression strategy.

Main Results:

  • Several small molecules and RNA-guided modifications have demonstrated efficacy in preclinical and clinical studies for nonsense suppression.
  • These agents promote the read-through of PTCs, potentially restoring protein function.
  • Box H/ACA RNA-guided pseudouridylation offers a novel approach to nonsense suppression.

Conclusions:

  • Therapeutic strategies targeting PTCs hold significant potential for treating a third of genetic disorders.
  • Further research is needed to overcome obstacles for broad clinical implementation of these read-through agents.
  • Nonsense suppression represents a promising therapeutic avenue for genetic diseases caused by PTCs.

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