PT  - JOURNAL ARTICLE
AU  - Mariana Conceição
AU  - Laura Forcina
AU  - Oscar P. B. Wiklander
AU  - Dhanu Gupta
AU  - Joel Z. Nordin
AU  - Graham McClorey
AU  - Imre Mäger
AU  - André Görgens
AU  - Per Lundin
AU  - Antonio Musarò
AU  - Matthew J. A. Wood
AU  - Samir EL Andaloussi
AU  - Thomas C. Roberts
TI  - Engineered extracellular vesicle decoy receptor-mediated modulation of the IL6 trans-signalling pathway in muscle
AID  - 10.1101/2020.06.09.142216
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.06.09.142216
4099  - http://biorxiv.org/content/early/2020/06/10/2020.06.09.142216.short
4100  - http://biorxiv.org/content/early/2020/06/10/2020.06.09.142216.full
AB  - The cytokine interleukin 6 (IL6) is a key mediator of inflammation that contributes to skeletal muscle pathophysiology. IL6 activates target cells by two different mechanisms, the classical and transsignalling pathways. While classical signalling is associated with the anti-inflammatory activities of the cytokine, the IL6 trans-signalling pathway mediates chronic inflammation and is therefore a target for therapeutic intervention. Extracellular vesicles (EVs) are natural, lipid-bound nanoparticles, with potential as targeted delivery vehicles for therapeutic macromolecules. Here, we engineered EVs to express IL6 signal transducer (IL6ST) decoy receptors to selectively inhibit the IL6 trans-signalling pathway. The potency of the IL6ST decoy receptor EVs was optimized by inclusion of a GCN4 dimerization domain and a peptide sequence derived from syntenin-1 which targets the decoy receptor to EVs. The resulting engineered EVs were able to efficiently inhibit activation of the IL6 transsignalling pathway in reporter cells, while having no effect on the IL6 classical signalling. IL6ST decoy receptor EVs, were also capable of blocking the IL6 trans-signalling pathway in C2C12 myoblasts and myotubes, thereby inhibiting the phosphorylation of STAT3 and partially reversing the anti-differentiation effects observed when treating cells with IL6/IL6R complexes. Treatment of a Duchenne muscular dystrophy mouse model with IL6ST decoy receptor EVs resulted in a reduction in STAT3 phosphorylation in the quadriceps and gastrocnemius muscles of these mice, thereby demonstrating in vivo activity of the decoy receptor EVs as a potential therapy. Taken together, this study reveals the IL6 trans-signalling pathway as a promising therapeutic target in DMD, and demonstrates the therapeutic potential of IL6ST decoy receptor EVs.Competing Interest StatementMJAW and SEA are founders of, and consultants for, Evox Therapeutics. IM, AG, and DG are consultants for Evox Therapeutics. MJAW, SEA, JZN, OW, AG, and DG are shareholders in Evox Therapeutics. The remaining authors declare no conflicts of interest.