Gene therapy progress and prospects: reprograming gene expression by trans-splicing

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 therapy: 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 trans-splice only a portion of the gene to be replaced; and the conversion of dominant-negative mutations to wild-type gene products.