Gene Therapy Progress and Prospects: Reprograming gene expression by trans-splicing

L G Mitchell, G J McGarrity
2005 Gene Therapy  
The term 'trans-splicing' encompasses several platform technologies that combine two RNA or protein molecules to generate a new, chimeric product. RNA trans-splicing reprograms the sequences of endogenous messenger mRNA or pre-mRNA, converting them to a new, desired gene product. Trans-splicing has broad applications, depending on the nature of the sequences that are inserted or trans-spliced to the defined target. Trans-splicing RNA therapy offers significant advantages over conventional gene
more » ... herapy: expression of the trans-spliced sequence is controlled by the endogenous regulation of the target pre-mRNA; reduction or elimination of undesirable ectopic expression; the ability to use smaller constructs that transsplice only a portion of the gene to be replaced; and the conversion of dominant-negative mutations to wild-type gene products. Nature Publishing Group All rights reserved 0969-7128/05 $30.00 www.nature.com/gt In brief Progress Spliceosome-mediated RNA trans-splicing (SMaRTt) can reprogram the 5 0 , 3 0 or internal coding sequences of a targeted transcript. The therapeutic potential of SMaRTt has been demonstrated in vivo in different systems. Trans-splicing confers the endogenous regulation of the targeted transcript on the sequence that is transspliced. Trans-splicing is a tool for molecular imaging. Improvements in ribozyme mediated trans-splicing have been demonstrated in vitro. New technologies for trans-splicing RNA and protein are being developed. High-capacity screens to identify more efficient transsplicing molecules have been developed. Prospects Development and clinical testing of RNA transsplicing therapeutics. High-capacity screens will see wider application to improve the specificity and efficiency of trans-splicing in the complex environment of human cells. Understanding of the naturally occurring transsplicing process may improve the design of new trans-splicing molecules.
doi:10.1038/sj.gt.3302596 pmid:16121205 fatcat:dhrwst6aubczbbjoorkcm2tp74