cmdooley.bsky.social
@cmdooley.bsky.social
4/5 🏥 Therapeutic Implications:
This TA mechanism opens new avenues: ASOs/ribozymes could enhance utrophin to compensate for dystrophin. Surprisingly, current exon-skipping therapies (e.g., eteplirsen) might reduce utrophin. #DrugDevelopment 3/5 💡 Key Experiments:
Splice-switching ASOs skipped exons, creating PTCs and raising utrophin levels.
Restoring the reading frame in patient cells reduced utrophin, showing TA’s role.
Self-cleaving ribozymes in minigenes also triggered utrophin. #ASO #RNA 2/5 🧪 How does it work?
By introducing premature stop codons (PTCs) in DMD mRNA, we induced mRNA decay via nonsense-mediated decay (NMD). This decay signals cells to boost UTRN (utrophin) transcription. Blocking NMD reversed utrophin upregulation! #GeneTherapy #CRISPR 1/? 🧬 New Breakthrough in Duchenne Muscular Dystrophy (DMD)!
Our new paper in
@Nature
reveals how utrophin—a dystrophin “backup”—is upregulated in DMD. The key? Transcriptional adaptation (TA), triggered by mutant mRNA decay, not protein loss.
[🔗 Link: www.nature.com/articles/s41... 