Regulated gene editing system

A system for editing a gene (e.g., altering expression of at least one gene product) having reduced off target effects comprising introducing into a cell having a target gene sequence

• a) a vector comprising a nucleic acid sequence encoding a nuclease, wherein the nucleic acid encoding the nuclease contains within its sequence a regulatory nucleic acid sequence having a first and second set of splice elements defining a first and second intron, wherein the first and second intron flank a sequence encoding a non-naturally occurring exon sequence containing an in-frame stop codon sequence, and wherein the first and second intron are spliced from the pre-mRNA message to produce an mRNA encoding a non-functional nuclease that contains an amino acid sequence encoded by the non-naturally occurring exon;
• and
• b) an oligonucleotide that binds to the regulatory nucleic acid sequence, wherein within the cell the oligonucleotide prevents splicing of the second set of splice elements from the mRNA, thereby producing an mRNA that lacks the exon and encodes a nuclease that is functional for gene editing of a target gene.