Methods and compositions are provided for generating novel nucleic acid molecules through targeted spliceosome mediated RNA splicing (SMaRT) that result in expression of a splicing isoform or variant thereof. The methods and compositions are based upon pre trans splicing molecules (PTMs) designed to interact with a target pre mRNA molecule and mediate a t splicing reaction generating a novel chimeric RNA molecule encoding a splicing isoform for the treatment of a variety of gene isoform induced diseases such as cancer.
