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Targeting RNA splicing for disease therapy.

Authors
  • Havens, Mallory A
  • Duelli, Dominik M
  • Hastings, Michelle L
Type
Published Article
Journal
Wiley Interdisciplinary Reviews - RNA
Publisher
Wiley (John Wiley & Sons)
Publication Date
Jan 01, 2013
Volume
4
Issue
3
Pages
247–266
Identifiers
DOI: 10.1002/wrna.1158
PMID: 23512601
Source
Medline
License
Unknown

Abstract

Splicing of pre-messenger RNA into mature messenger RNA is an essential step for the expression of most genes in higher eukaryotes. Defects in this process typically affect cellular function and can have pathological consequences. Many human genetic diseases are caused by mutations that cause splicing defects. Furthermore, a number of diseases are associated with splicing defects that are not attributed to overt mutations. Targeting splicing directly to correct disease-associated aberrant splicing is a logical approach to therapy. Splicing is a favorable intervention point for disease therapeutics, because it is an early step in gene expression and does not alter the genome. Significant advances have been made in the development of approaches to manipulate splicing for therapy. Splicing can be manipulated with a number of tools including antisense oligonucleotides, modified small nuclear RNAs (snRNAs), trans-splicing, and small molecule compounds, all of which have been used to increase specific alternatively spliced isoforms or to correct aberrant gene expression resulting from gene mutations that alter splicing. Here we describe clinically relevant splicing defects in disease states, the current tools used to target and alter splicing, specific mutations and diseases that are being targeted using splice-modulating approaches, and emerging therapeutics.

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