Duchenne muscular dystrophy (DMD) is a muscle-degenerating disease caused by mutations in DMD/dystrophin. Utrophin (UTRN), the genetic and functional paralog of DMD, is upregulated in some DMD patients. To further investigate this UTRN upregulation, we first developed an inducible mRNA degradation system for DMD by introducing a premature termination codon (PTC) in one of its alternatively spliced exons. Inclusion of the PTC-containing exon triggers DMD mutant mRNA decay and UTRN upregulation. Notably, blocking nonsense-mediated mRNA decay results in the reversal of UTRN upregulation, whereas overexpressing DMD does not. Furthermore, overexpressing DMDPTC minigenes in wild-type cells causes UTRN upregulation, as does a wild-type DMD minigene containing a self-cleaving ribozyme. To place these findings in a therapeutic context, we used splice-switching antisense oligonucleotides (ASOs) to induce the skipping of out-of-frame exons of DMD, aiming to introduce PTCs. We found that these ASOs cause UTRN upregulation. In addition, when using an ASO to restore the DMD reading frame in myotubes derived from a DMDΔE52 patient, an actual DMD treatment, UTRN upregulation was reduced. Altogether, these results indicate that an mRNA decay-based mechanism called transcriptional adaptation plays a key role in UTRN upregulation in DMDPTC patients, and highlight an unexplored therapeutic application of ASOs, as well as ribozymes, in inducing genetic compensation via transcriptional adaptation. This presentation will focus on published (see above) and unpublished data generated in the context of our effort to use an endogenous genetic compensation mechanism (i.e., transcriptional adaptation) as a new therapeutic approach for DMD patients.