Publications [#177507] of Bruce A Sullenger

Papers Published

1. MN Kierlin-Duncan, BA Sullenger, Using 5'-PTMs to repair mutant beta-globin transcripts., RNA (New York, N.Y.), vol. 13 no. 8 (August, 2007), pp. 1317-27, ISSN 1355-8382 [doi]
   (last updated on 2013/05/16)

   Abstract:
   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.

   Keywords:
   Cell Line • Exons • Globins • Humans • Introns • Mutation* • RNA, Messenger • Spliceosomes • Trans-Splicing* • genetics* • metabolism