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Using 5'-PTMs to repair mutant beta-globin transcripts.

Publication ,  Journal Article
Kierlin-Duncan, MN; Sullenger, BA
Published in: RNA
August 2007

Trans-splicing has been used to repair mutant RNA transcripts via competition for the spliceosome using pre-trans-splicing molecules, or "PTMs." Previous studies have demonstrated that functional PTMs can be designed for either 3'- or 5'-exon replacement, with a vast majority of the work to date focusing on repair of mutations within internal exons and via 3'-exon replacement. Here, we describe the first use of trans-splicing to target the first exon and intron of a therapeutically relevant gene and repair the mutant RNA by 5'-exon replacement. Our results show that 5'-PTMs can be designed to repair mutations in the beta-globin transcript involved in sickle cell anemia and beta-thalassemia while providing insight into considerations for competition between trans- versus cis-splicing in mammalian cells. Target transcripts with impaired cis-splicing capabilities, like those produced in some forms of beta-thalassemia, are more efficiently repaired via trans-splicing than targets in which cis-splicing is unaffected as with sickle beta-globin. This study reveals desirable characteristics in substrate RNAs for trans-splicing therapeutics as well as provides an opportunity for further exploration into general splicing mechanisms via 5'-PTMs.

Duke Scholars

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Published In

RNA

DOI

ISSN

1355-8382

Publication Date

August 2007

Volume

13

Issue

8

Start / End Page

1317 / 1327

Location

United States

Related Subject Headings

  • Trans-Splicing
  • Spliceosomes
  • RNA, Messenger
  • Mutation
  • Introns
  • Humans
  • Globins
  • Exons
  • Developmental Biology
  • Cell Line
 

Citation

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ICMJE
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Kierlin-Duncan, M. N., & Sullenger, B. A. (2007). Using 5'-PTMs to repair mutant beta-globin transcripts. RNA, 13(8), 1317–1327. https://doi.org/10.1261/rna.525607
Kierlin-Duncan, Monique N., and Bruce A. Sullenger. “Using 5'-PTMs to repair mutant beta-globin transcripts.RNA 13, no. 8 (August 2007): 1317–27. https://doi.org/10.1261/rna.525607.
Kierlin-Duncan MN, Sullenger BA. Using 5'-PTMs to repair mutant beta-globin transcripts. RNA. 2007 Aug;13(8):1317–27.
Kierlin-Duncan, Monique N., and Bruce A. Sullenger. “Using 5'-PTMs to repair mutant beta-globin transcripts.RNA, vol. 13, no. 8, Aug. 2007, pp. 1317–27. Pubmed, doi:10.1261/rna.525607.
Kierlin-Duncan MN, Sullenger BA. Using 5'-PTMs to repair mutant beta-globin transcripts. RNA. 2007 Aug;13(8):1317–1327.

Published In

RNA

DOI

ISSN

1355-8382

Publication Date

August 2007

Volume

13

Issue

8

Start / End Page

1317 / 1327

Location

United States

Related Subject Headings

  • Trans-Splicing
  • Spliceosomes
  • RNA, Messenger
  • Mutation
  • Introns
  • Humans
  • Globins
  • Exons
  • Developmental Biology
  • Cell Line