En Route to Targeted Ribosome Editing to Replenish Skin Anchor Protein LAMB3 in Junctional Epidermolysis Bullosa

• Main Authors: Bjoern Wimmer (Author), Andreas Friedrich (Author), Katharina Poeltner (Author), Genevieve Edobor (Author), Claudia Mosshammer (Author), Gazmend Temaj (Author), Adriana Rathner (Author), Thomas Karl (Author), Jan Krauss (Author), Joerg von Hagen (Author), Christopher Gerner (Author), Michael Breitenbach (Author), Helmut Hintner (Author), Johann W. Bauer (Author), Hannelore Breitenbach-Koller (Author)
• פורמט: ספר
• יצא לאור: Elsevier, 2024-01-01T00:00:00Z.
• נושאים: article
• גישה מקוונת: Connect to this object online.

סיכום

Severe junctional epidermolysis bullosa is a rare genetic, postpartum lethal skin disease, predominantly caused by nonsense/premature termination codon (PTC) sequence variants in LAMB3 gene. LAMB3 encodes LAMB3, the β subunit of epidermal-dermal skin anchor laminin 332. Most translational reads of a PTC mRNA deliver truncated, nonfunctional proteins, whereas an endogenous PTC readthrough mechanism produces full-length protein at minimal and insufficient levels. Conventional translational readthrough-inducing drugs amplify endogenous PTC readthrough; however, translational readthrough-inducing drugs are either proteotoxic or nonselective. Ribosome editing is a more selective and less toxic strategy. This technique identified ribosomal protein L35/uL29 (ie, RpL35) and RpL35-ligands repurposable drugs artesunate and atazanavir as molecular tools to increase production levels of full-length LAMB3. To evaluate ligand activity in living cells, we monitored artesunate and atazanavir treatment by dual luciferase reporter assays. Production levels of full-length LAMB3 increased up to 200% upon artesunate treatment, up to 150% upon atazanavir treatment, and up to 170% upon combinatorial treatment of RpL35 ligands at reduced drug dosage, with an unrelated PTC reporter being nonresponsive. Proof of bioactivity of RpL35 ligands in selective increase of full-length LAMB3 provides the basis for an alternative, targeted therapeutic route to replenish LAMB3 in severe junctional epidermolysis bullosa.

תאור פריט

2667-0267
10.1016/j.xjidi.2023.100240