Splice-switching oligonucleotides act on the endogenous Bcl-x gene to enforce splice site choice of the Bcl-xS. The region of the Bcl-x pre-mRNA that includes two alternative 5' splice sites (SSs) that produce either the constitutive long (L) splice variant or the alternative short (S) splice variant is schematically depicted. Selection of an intron-proximal L 5' splice site (SS) results in production of the Bcl-xL isoform (at right) whereas the selection of the proximal S 5' SS results in the production of the Bcl-xS isoform (at left). The SSO oligonucleotide that base pair with the major L splice site forces splicing from the distal 5' SS and induces expression of the endogenous Bcl-xS isoform (at left). The Bcl-xL gene product has anti-apoptotic activity while the Bcl-xS gene product possesses pro-apoptotic activity.