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RNA-targeted drugs

The Essence of correction

Nature Reviews Drug Discovery volume 2, page 170 (2003)Cite this article

Now, in Nature Structural Biology, Adrian Krainer and Luca Cartegni describe the development of ESSENCE (exon-specific silencing enhancement by small chimeric effectors), which can correct these genetic typos by emulating the function of essential splicing factors called serine/arginine-rich (SR) proteins. SR proteins act at several steps during normal and alternative splicing — they work by binding to sequences called exonic splicing enhancers (ESEs) through their RNA-binding domains and recruiting the cutting-and-pasting components of the splicing machinery through protein–protein interactions mediated by an RS domain (a domain characterized by several Arg–Ser dipeptides).

To restore normal splicing in exon-skipping models, Krainer and Cartegni fused a synthetic RS domain to an antisense fragment that binds to specific exons. They tested the ESSENCE concept first in the breast cancer 1, early onset gene ( BRCA1 ), in which a natural mutation in an ESE in exon 18 causes the exclusion of this exon from the mRNA. The addition of an ESSENCE compound with the exon-18-specific antisense fragment restored accurate splicing in a dose-dependent manner in vitro, and required both the antisense-targeting fragment and the synthesized RS-protein-recruitment domain to carry out its function.

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References

ORIGINAL RESEARCH PAPERS

  1. Cartegni, L. & Krainer, A. R. Correction of disease-associated exon skipping by synthetic exon-specific activators. Nature Struct. Biol. 10, 120–125 (2003)

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FURTHER READING

  1. Cartegni, L., Chew, S. L. & Krainer, A. R. Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nature Rev. Genet. 3, 285–298 (2002)

    Article  CAS  Google Scholar 

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Authors
  1. Simon Frantz
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Frantz, S. The Essence of correction. Nat Rev Drug Discov 2, 170 (2003). https://doi.org/10.1038/nrd1029

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  • DOI: https://doi.org/10.1038/nrd1029

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