Progressive muscle degeneration, muscle weakness, up to cardiac fibrosis and heart failure can be main consequences of Duchenne muscular dystrophy (DMD), a genetic disorder causing mutations in the dystrophin protein. Lara Falcucci and Colleagues found that transcriptional adaptation (TA) plays a role in DMD and can be considered for treatment.

TA is a recently identified mode of genetic compensation in which mRNA degradation, rather than protein loss, can drive the upregulation of functional paralogs to compensate for gene inactivation.

DMD mRNA degradation—triggered by frameshift-inducing Cas9 mutations, splice-switching antisense oligonucleotides (ASOs) disrupting the reading frame, or a self-cleaving ribozyme-containing DMD minigene—induces the upregulation of utrophin (UTRN), a functional paralog capable of compensating for the loss of dystrophin.

Notably, in DMD patient-derived myotubes with an exon 52 deletion, which naturally exhibit UTRN upregulation, ASO-mediated exon 51 skipping—similar to the FDA-approved ASO eteplirsen—not only restored the DMD mRNA reading frame but also attenuated UTRN upregulation, potentially counteracting some therapeutic benefits.

Altogether, these findings highlight the importance of considering TA in treatment design—either by avoiding interference with it or harnessing it for therapeutic benefit.

Find the full article here: https://www.nature.com/articles/s41586-024-08539-x